NUDT22 promotes cancer growth through pyrimidine salvage.

The NUDIX hydrolase NUDT22 converts UDP-glucose into glucose-1-phosphate and the pyrimidine nucleotide uridine monophosphate but a biological significance for this biochemical reaction has not yet been established. Glucose-1-phosphate is an important metabolite for energy and biomass production through glycolysis and nucleotides required for DNA replication are produced through energetically expensive de novo or energy-efficient salvage pathways. Here, we describe p53-regulated pyrimidine salvage through NUDT22-dependent hydrolysis of UDP-glucose to maintain cancer cell growth and to prevent replication stress. NUDT22 expression is consistently elevated in cancer tissues and high NUDT22 expression correlates with worse survival outcomes in patients indicating an increased dependency of cancer cells to NUDT22. Furthermore, we show that NUDT22 transcription is induced after inhibition of glycolysis, MYC-mediated oncogenic stress, and DNA damage directly through p53. NUDT22-deficient cancer cells suffer from growth retardation, S-phase delay, and slower DNA replication fork speed. Uridine supplementation rescues replication fork progression and alleviates replication stress and DNA damage. Conversely, NUDT22 deficiency sensitizes cells to de novo pyrimidine synthesis inhibition in vitro and reduces cancer growth in vivo. In conclusion, NUDT22 maintains pyrimidine supply in cancer cells and depletion of NUDT22 leads to genome instability. Targeting NUDT22 therefore has high potential for therapeutic applications in cancer therapy.

BET inhibitor trotabresib in heavily pretreated patients with solid tumors and diffuse large B-cell lymphomas.

Bromodomain and extraterminal proteins (BET) play key roles in regulation of gene expression, and may play a role in cancer-cell proliferation, survival, and oncogenic progression. CC-90010-ST-001 (NCT03220347) is an open-label phase I study of trotabresib, an oral BET inhibitor, in heavily pretreated patients with advanced solid tumors and relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Primary endpoints were the safety, tolerability, maximum tolerated dose, and RP2D of trotabresib. Secondary endpoints were clinical benefit rate (complete response [CR] + partial response [PR] + stable disease [SD] of ≥4 months' duration), objective response rate (CR + PR), duration of response or SD, progression-free survival, overall survival, and the pharmacokinetics (PK) of trotabresib. In addition, part C assessed the effects of food on the PK of trotabresib as a secondary endpoint. The dose escalation (part A) showed that trotabresib was well tolerated, had single-agent activity, and determined the recommended phase 2 dose (RP2D) and schedule for the expansion study. Here, we report long-term follow-up results from part A (N = 69) and data from patients treated with the RP2D of 45 mg/day 4 days on/24 days off or an alternate RP2D of 30 mg/day 3 days on/11 days off in the dose-expansion cohorts (parts B [N = 25] and C [N = 41]). Treatment-related adverse events (TRAEs) are reported in almost all patients. The most common severe TRAEs are hematological. Toxicities are generally manageable, allowing some patients to remain on treatment for ≥2 years, with two patients receiving ≥3 years of treatment. Trotabresib monotherapy shows antitumor activity, with an ORR of 13.0% (95% CI, 2.8-33.6) in patients with R/R DLBCL (part B) and an ORR of 0.0% (95% CI, 0.0-8.6) and a CBR of 31.7% (95% CI, 18.1-48.1) in patients with advanced solid tumors (part C). These results support further investigation of trotabresib in combination with other anticancer agents.

Trotabresib, an oral potent bromodomain and extraterminal inhibitor, in patients with high-grade gliomas: A phase I, "window-of-opportunity" study.

BACKGROUND: The bromodomain and extraterminal protein (BET) inhibitor trotabresib has demonstrated antitumor activity in patients with advanced solid tumors, including high-grade gliomas. CC-90010-GBM-001 (NCT04047303) is a phase I study investigating the pharmacokinetics, pharmacodynamics, and CNS penetration of trotabresib in patients with recurrent high-grade gliomas scheduled for salvage resection. METHODS: Patients received trotabresib 30 mg/day on days 1-4 before surgery, followed by maintenance trotabresib 45 mg/day 4 days on/24 days off after surgery. Primary endpoints were plasma pharmacokinetics and trotabresib concentrations in resected tissue. Secondary and exploratory endpoints included safety, pharmacodynamics, and antitumor activity. RESULTS: Twenty patients received preoperative trotabresib and underwent resection with no delays or cancelations of surgery; 16 patients received maintenance trotabresib after recovery from surgery. Trotabresib plasma pharmacokinetics were consistent with previous data. Mean trotabresib brain tumor tissue:plasma ratio was 0.84 (estimated unbound partition coefficient [KPUU] 0.37), and modulation of pharmacodynamic markers was observed in blood and brain tumor tissue. Trotabresib was well tolerated; the most frequent grade 3/4 treatment-related adverse event during maintenance treatment was thrombocytopenia (5/16 patients). Six-month progression-free survival was 12%. Two patients remain on treatment with stable disease at cycles 25 and 30. CONCLUSIONS: Trotabresib penetrates the blood-brain-tumor barrier in patients with recurrent high-grade glioma and demonstrates target engagement in resected tumor tissue. Plasma pharmacokinetics, blood pharmacodynamics, and safety were comparable with previous results for trotabresib in patients with advanced solid tumors. Investigation of adjuvant trotabresib + temozolomide and concomitant trotabresib + temozolomide + radiotherapy in patients with newly diagnosed glioblastoma is ongoing (NCT04324840).

Trotabresib (CC-90010) in combination with adjuvant temozolomide or concomitant temozolomide plus radiotherapy in patients with newly diagnosed glioblastoma.

Background: Standard-of-care treatment for newly diagnosed glioblastoma (ndGBM), consisting of surgery followed by radiotherapy (RT) and temozolomide (TMZ), has improved outcomes compared with RT alone; however, prognosis remains poor. Trotabresib, a novel bromodomain and extraterminal inhibitor, has demonstrated antitumor activity in patients with high-grade gliomas. Methods: In this phase Ib, dose-escalation study (NCT04324840), we investigated trotabresib 15, 30, and 45 mg combined with TMZ in the adjuvant setting and trotabresib 15 and 30 mg combined with TMZ+RT in the concomitant setting in patients with ndGBM. Primary endpoints were to determine safety, tolerability, maximum tolerated dose, and/or recommended phase II dose (RP2D) of trotabresib. Secondary endpoints were assessment of preliminary efficacy and pharmacokinetics. Pharmacodynamics were investigated as an exploratory endpoint. Results: The adjuvant and concomitant cohorts enrolled 18 and 14 patients, respectively. Trotabresib in combination with TMZ or TMZ+RT was well tolerated; most treatment-related adverse events were mild or moderate. Trotabresib pharmacokinetics and pharmacodynamics in both settings were consistent with previous data for trotabresib monotherapy. The RP2D of trotabresib was selected as 30 mg 4 days on/24 days off in both settings. At last follow-up, 5 (28%) and 6 (43%) patients remain on treatment in the adjuvant and concomitant settings, respectively, with 1 patient in the adjuvant cohort achieving complete response. Conclusions: Trotabresib combined with TMZ in the adjuvant setting and with TMZ+RT in the concomitant setting was safe and well tolerated in patients with ndGBM, with encouraging treatment durations. Trotabresib 30 mg was established as the RP2D in both settings.

Midline extraperitoneal approach to retroperitoneal pathology - broadening the horizons.

We present an explanation of approach to open midline extraperitoneal surgery for the management of retroperitoneal pathology. Included are diagrammatic and intra-operative images to better explain the approach, as well as discussion regarding the technique.

Small-molecule activation of OGG1 increases oxidative DNA damage repair by gaining a new function.

Oxidative DNA damage is recognized by 8-oxoguanine (8-oxoG) DNA glycosylase 1 (OGG1), which excises 8-oxoG, leaving a substrate for apurinic endonuclease 1 (APE1) and initiating repair. Here, we describe a small molecule (TH10785) that interacts with the phenylalanine-319 and glycine-42 amino acids of OGG1, increases the enzyme activity 10-fold, and generates a previously undescribed ß,δ-lyase enzymatic function. TH10785 controls the catalytic activity mediated by a nitrogen base within its molecular structure. In cells, TH10785 increases OGG1 recruitment to and repair of oxidative DNA damage. This alters the repair process, which no longer requires APE1 but instead is dependent on polynucleotide kinase phosphatase (PNKP1) activity. The increased repair of oxidative DNA lesions with a small molecule may have therapeutic applications in various diseases and aging.

Electrical neuromodulation in bladder dysfunction: Mapping the state-of-the-art with bibliometric analysis of field and top 100 cited articles.

AIMS: Electrical neuromodulation of bladder function has been extensively investigated in the literature. To date, there has been no characterization of the field, and there is a lack of bibliometric literature to guide future studies. We directed this scientometric analysis to characterize the distribution, characteristics and relationships of the field, with subanalysis of top 100 articles. METHODS: The Web of Science Core Collection of the Thompson Reuters Web of Science was searched and analyzed to determine distributions and characteristics of clinical research investigating electrical neuromodulation in bladder dysfunction. Field citation and coauthorship networks were mapped, and recent citation bursts of the past decade are described. The top 100 cited articles were categorized, with level of evidence rating system applied. RESULTS: A total of 872 articles published from 1949 until October 2020 were included in field analysis. Europe demonstrated the highest continental productivity within field (n = 539, 61.81%), and the United States the top nation (35.55% of field, 39.24% of top 100 articles). The Journal of Urology has historically published the most articles in the field (n = 150, 17.20%), and top 100 articles (n = 41, 40.20%). Top 100 articles reported studies of neuromodulation effects via sacral neuromodulation (n = 59); of non-neurological bladder dysfunction (n = 72); urinary incontinence (n = 92), frequency (n = 73) and urgency (n = 68) symptomology. CONCLUSIONS: Analysis of electrical neuromodulation of bladder dysfunction literature reveals historical development, core research clusters and relationships, and an increase in publication activity over past decades.

NEIL1 and NEIL2 Are Recruited as Potential Backup for OGG1 upon OGG1 Depletion or Inhibition by TH5487.

DNA damage caused by reactive oxygen species may result in genetic mutations or cell death. Base excision repair (BER) is the major pathway that repairs DNA oxidative damage in order to maintain genomic integrity. In mammals, eleven DNA glycosylases have been reported to initiate BER, where each recognizes a few related DNA substrate lesions with some degree of overlapping specificity. 7,8-dihydro-8-oxoguanine (8-oxoG), one of the most abundant DNA oxidative lesions, is recognized and excised mainly by 8-oxoguanine DNA glycosylase 1 (OGG1). Further oxidation of 8-oxoG generates hydantoin lesions, which are recognized by NEIL glycosylases. Here, we demonstrate that NEIL1, and to a lesser extent NEIL2, can potentially function as backup BER enzymes for OGG1 upon pharmacological inhibition or depletion of OGG1. NEIL1 recruitment kinetics and chromatin binding after DNA damage induction increase in cells treated with OGG1 inhibitor TH5487 in a dose-dependent manner, whereas NEIL2 accumulation at DNA damage sites is prolonged following OGG1 inhibition. Furthermore, depletion of OGG1 results in increased retention of NEIL1 and NEIL2 at damaged chromatin. Importantly, oxidatively stressed NEIL1- or NEIL2-depleted cells show excessive genomic 8-oxoG lesions accumulation upon OGG1 inhibition, suggesting a prospective compensatory role for NEIL1 and NEIL2. Our study thus exemplifies possible backup mechanisms within the base excision repair pathway.

Small molecule inhibitor of OGG1 blocks oxidative DNA damage repair at telomeres and potentiates methotrexate anticancer effects.

The most common oxidative DNA lesion is 8-oxoguanine which is mainly recognized and excised by the 8-oxoG DNA glycosylase 1 (OGG1), initiating the base excision repair (BER) pathway. Telomeres are particularly sensitive to oxidative stress (OS) which disrupts telomere homeostasis triggering genome instability. In the present study, we have investigated the effects of inactivating BER in OS conditions, by using a specific inhibitor of OGG1 (TH5487). We have found that in OS conditions, TH5487 blocks BER initiation at telomeres causing an accumulation of oxidized bases, that is correlated with telomere losses, micronuclei formation and mild proliferation defects. Moreover, the antimetabolite methotrexate synergizes with TH5487 through induction of intracellular reactive oxygen species (ROS) formation, which potentiates TH5487-mediated telomere and genome instability. Our findings demonstrate that OGG1 is required to protect telomeres from OS and present OGG1 inhibitors as a tool to induce oxidative DNA damage at telomeres, with the potential for developing new combination therapies for cancer treatment.

Double partial nephrectomy in allograft transplanted kidney.

A 61-year-old female presented with an incidental anterior mid pole renal mass on ultrasound. She had previously undergone live directed donor renal transplantation 13 years prior. As the 10 year survival of living transplant recipients increases, malignancy presentations will continue to rise. Nephron sparing surgery in renal allografts is sparse due to difficult operative dissection and complicated hila vascular control. We present the use of manual atraumatic graded bowel clamp pressure around the resected tumour as a viable option to safely perform partial nephrectomy in a transplanted kidney.

Association between ureteric stent dwell time and urinary tract infection.

BACKGROUND: Ureteric stone obstruction commonly presents to the emergency department, with definitive management often involving ureteroscopy and laser lithotripsy. Insertion of a ureteric stent prior to staged lithotripsy is commonly performed in the public healthcare system. Foreign bodies in the urinary tract are also known to increase urinary tract infection (UTI) risk. This study aims to evaluate the association between stent dwell time and UTI prior to lithotripsy. METHODS: The medical records of all patients who were treated for ureteric stones with initial stent insertion and staged lithotripsy, from 1 January 2018 to 30 June 2019 at a single tertiary centre, by eight urologists were retrospectively reviewed. Demographic features, disease factors and urine culture data were collected and analysed. RESULTS: Of the 172 patients (median age 56.7 years) identified, one-third had a positive pre-stent urine culture. Twenty-three percent had a positive pre-lithotripsy urine culture with 38% of females compared with 15% of males having a positive culture (P = 0.001). Only 4.3% of patients had a pre-lithotripsy UTI when the stent dwell time was less than 1 month compared with 26.2% when ureteric stents were in situ for longer than 1 month (P = 0.021). The correlation between ureteric stent dwell time and pre-lithotripsy UTI was not linear. Patient comorbidities, stone size, burden and location were not statistically correlated to pre-lithotripsy UTI. CONCLUSION: In delayed two-staged surgical management of acute urolithiasis, optimal ureteric stent dwell time is less than 1 month to reduce pre-lithotripsy UTI. Female gender is an independent risk factor for pre-lithotripsy UTI.

Percutaneous Ventricular Assist Device vs. Intra-Aortic Balloon Pump for Hemodynamic Support in Acute Myocardial Infarction-Related Cardiogenic Shock and Coexistent Atrial Fibrillation: A Nationwide Propensity-Matched Analysis'.

BACKGROUND: Patients suffering an acute myocardial infarction complicated by cardiogenic shock (AMICS) may experience clinical deterioration with concomitant atrial fibrillation (AF). Recent data suggest that percutaneous ventricular assist devices (pVADs) provide superior hemodynamic support over intra-aortic balloon pump (IABP) in AMICS. In patients with AF+AMICS, however, outcomes data comparing these two devices remain limited. METHODS: Using the National Inpatient Sample datasets (2008-2014) and a propensity-score matched analysis, we compared the outcomes of AMICS+AF hospitalized patients undergoing PCI with pVAD vs. IABP support. RESULTS: A total of 12,842 AMICS+AF patients were identified (pVAD=468, IABP=12,374). The matched groups (pVAD=443, IABP=443) were comparable in terms of mean age (70.3 ± 12.0 vs. 70.4 ± 11.0yrs, p = 0.92). The utilization of pVAD was higher in whites but lower in Medicare/Medicaid beneficiaries as compared to IABP. The pVAD group demonstrated higher rates of obesity (13.6% vs. 7.8%, p = 0.006) and dyslipidemia (48.4% vs. 41.8%, p = 0.05). There was no difference in the in-hospital mortality (40.5% vs. 36.8%, p = 0.25); however, pVAD group had a lower incidence of post-procedural MI and higher incidences of stroke (7.8% vs. 4.4%, p = 0.03), hemorrhage (5.6% vs. 2.3%, p = 0.01), discharges to home health care (13.5% vs. 10.1%, p<0.001) and to other facilities (29.1% vs. 24.9%, p<0.001) as compared to IABP group. There was no difference between the groups in terms of mean length of stay or hospital charges. CONCLUSIONS: All-cause inpatient mortality was similar in AMICS+AF patients undergoing PCI who were treated with either pVAD or IABP. The pVAD group, however, experienced more complications while consuming greater healthcare resources.

Sickle cell disease-associated arrhythmias and in-hospital outcomes: Insights from the National Inpatient Sample.

BACKGROUND: The frequency and temporal trend in the prevalence of arrhythmias and associated in-hospital outcomes in patients with sickle cell disease (SCD) have never been quantified. METHODS: Our study cohort of SCD patients and sub-types of arrhythmias were derived from the 2010-2014 National Inpatient Sample using relevant diagnostic codes. The frequency and trends of arrhythmia and odds of inpatient mortality were measured. RESULTS: A total of 891 450 hospitalized SCD patients were identified, of which, 55 616 (6.2%) patients experienced arrhythmias. The SCD cohort with arrhythmia demonstrated higher all-cause mortality (2.7% vs 0.4%; adjusted OR 2.53, 95% CI 2.15-2.97, P < .001), prolonged hospital stays (6.9 vs 5.0 days) and higher hospital charges ($53 871 vs $30 905) relative to those without arrhythmias (P < .001).The frequency of supraventricular arrhythmia (AFib, SVT, and AF) and ventricular arrhythmia (VFib and VT) were 1893 and 362 per 100 000 SCD-related admissions, respectively. Unspecified arrhythmias (4126) were seen most frequently followed by AFib (1622) per 100 000 SCD-related admissions. From 2010 to 2014, the frequency of any arrhythmias and atrial fibrillation in hospitalized SCD patients relatively increased by 29.6% and 38.5%, respectively. There was nearly a twofold (2.4% in 2010 to 5.0% in 2014) increase in the frequency of arrhythmia among patients aged <18 years. The frequency of arrhythmias in hospitalized male and female SCD patients relatively increased by 28.8% and 31.4%, respectively (P trend < .001). CONCLUSIONS: The frequency of arrhythmias among SCD patients is on the rise with worse hospitalization outcomes, including higher in-hospital mortality and higher resource utilization as compared to those without arrhythmias.

Targeting OGG1 arrests cancer cell proliferation by inducing replication stress.

Altered oncogene expression in cancer cells causes loss of redox homeostasis resulting in oxidative DNA damage, e.g. 8-oxoguanine (8-oxoG), repaired by base excision repair (BER). PARP1 coordinates BER and relies on the upstream 8-oxoguanine-DNA glycosylase (OGG1) to recognise and excise 8-oxoG. Here we hypothesize that OGG1 may represent an attractive target to exploit reactive oxygen species (ROS) elevation in cancer. Although OGG1 depletion is well tolerated in non-transformed cells, we report here that OGG1 depletion obstructs A3 T-cell lymphoblastic acute leukemia growth in vitro and in vivo, validating OGG1 as a potential anti-cancer target. In line with this hypothesis, we show that OGG1 inhibitors (OGG1i) target a wide range of cancer cells, with a favourable therapeutic index compared to non-transformed cells. Mechanistically, OGG1i and shRNA depletion cause S-phase DNA damage, replication stress and proliferation arrest or cell death, representing a novel mechanistic approach to target cancer. This study adds OGG1 to the list of BER factors, e.g. PARP1, as potential targets for cancer treatment.

OGG1 Inhibitor TH5487 Alters OGG1 Chromatin Dynamics and Prevents Incisions.

8-oxoguanine DNA glycosylase (OGG1) is the main DNA glycosylase responsible for the excision of 7,8-dihydro-8-oxoguanine (8-oxoG) from duplex DNA to initiate base excision repair. This glycosylase activity is relevant in many pathological conditions including cancer, inflammation, and neurodegenerative diseases. To have a better understanding of the role of OGG1, we previously reported TH5487, a potent active site inhibitor of OGG1. Here, we further investigate the consequences of inhibiting OGG1 with TH5487. TH5487 treatment induces accumulation of genomic 8-oxoG lesions. Furthermore, it impairs the chromatin binding of OGG1 and results in lower recruitment of OGG1 to regions of DNA damage. Inhibiting OGG1 with TH5487 interferes with OGG1's incision activity, resulting in fewer DNA double-strand breaks in cells exposed to oxidative stress. This study validates TH5487 as a potent OGG1 inhibitor that prevents the repair of 8-oxoG and alters OGG1-chromatin dynamics and OGG1's recruitment kinetics.

Nationwide Trends in Prevalent Cardiovascular Risk Factors and Diseases in Young Adults: Differences by Sex and Race and In-Hospital Outcomes.

OBJECTIVES: Prevalence and trends in all cardiovascular disease (CVD) risk factors among young adults (18-39 years) have not been evaluated on a large scale stratified by sex and race. The aim of this study was to establish the prevalence and temporal trend of CVD risk factors in US inpatients younger than 40 years of age from 2007 through 2014 with racial and sex-based distinctions. In addition, the impact of these risk factors on inpatient outcomes and healthcare resource utilization was explored. METHODS: A cross-sectional nationwide analysis of all hospitalizations, comorbidities, and complications among young adults from 2007 to 2014 was performed. The primary outcomes were frequency, trends, and race- and sex-based differences in coexisting CVD risk factors. Coprimary outcomes were trends in all-cause mortality, acute myocardial infarction, arrhythmia, stroke, and venous thromboembolism in young adults with CVD risk factors. Secondary outcomes were demographics and resource utilization in young adults with versus without CVD risk factors. RESULTS: Of 63 million hospitalizations (mean 30.5 [standard deviation 5.9] years), 27% had at least one coexisting CVD risk factor. From 2007 to 2014, admission frequency with CVD risk factors increased from 42.8% to 55.1% in males and from 16.2% to 24.6% in females. Admissions with CVD risk were higher in male (41.4% vs 15.9%) and white (58.4% vs 53.8%) or African American (22.6% vs 15.9%) patients compared with those without CVD risk. Young adults in the Midwest (23.9% vs 21.1%) and South (40.8% vs 37.9%) documented comparatively higher hospitalizations rates with CVD risk. Young adults with CVD risk had higher all-cause in-hospital mortality (0.4% vs. 0.3%) with a higher average length of stay (4.3 vs 3.2 days) and charges per admission ($30,074 vs $20,124). CONCLUSIONS: Despite modern advances in screening, management, and interventional measures for CVD, rising trends in CVD risk factors across all sex and race/ethnic groups call for attention by preventive cardiologists.

Urethral caruncle with intestinal metaplasia: A case report and literature review.

A 66-year-old female presented with a urethral caruncle. Histological features of incomplete intestinal metaplasia were reported. Only five previous cases of intestinal metaplasia in urethral caruncles have been reported. The mechanism of this tissue transformation remains unclear but theorised aetiologies include embryological and infective causes. Intestinal metaplasia carries a malignant potential in other organs, most notably the bladder. Therefore we recommend urethral caruncles be completely excised with prolonged follow up for atypical variants.

Contemporary Pharmacologic Management of Heart Failure with Reduced Ejection Fraction: A Review.

Heart failure with reduced ejection fraction (HFrEF) is defined as the presence of typical symptoms of heart failure (HF) and a left ventricular ejection fraction ≤ 40%. HFrEF patients constitute approximately 50% of all patients with clinical HF. Despite breakthrough discoveries and advances in the pharmacologic management of HF, HFrEF patients continue to pose a significant economic burden due to a progressive disease characterized by recurrent hospitalizations and need for advanced therapy. Although there are effective, guideline-directed medical therapies for patients with HFrEF, a significant proportion of these patients are either not on appropriate medications' combination or on optimal tolerable medications' doses. Since the morbidity and mortality benefits of some of the pharmacologic therapies are dose-dependent, optimal medical therapy is required to impact the burden of disease, quality of life, prognosis, and to curb health care expenditure. In this review, we summarize landmark trials that have impacted the management of HF and we review contemporary pharmacologic management of patients with HFrEF. We also provide insight on general considerations in the management of HFrEF in specific populations. We searched PubMed, Scopus, Medline and Cochrane library for relevant articles published until April 2019 using the following key words "heart failure", "management", "treatment", "device therapy", "reduced ejection fraction", "guidelines", "guideline directed medical therapy", "trials" either by itself or in combination. We also utilized the cardiology trials portal to identify trials related to heart failure. We reviewed guidelines, full articles, review articles and clinical trials and focused on the pharmacologic management of HFrEF.