-
1.
Post hoc analysis of patients with rheumatoid arthritis under clinical remission in two Japanese Phase 3 trials of peficitinib treatment (RAJ3 and RAJ4).
Tanaka, Y, Takeuchi, T, Morita, Y, Kato, D, Kaneko, Y, Terada, W
Modern rheumatology. 2024;(3):453-465
Abstract
OBJECTIVE We evaluated remission rates and their relationship with baseline characteristics in patients with rheumatoid arthritis treated with the oral Janus kinase inhibitor peficitinib. METHODS This post hoc analysis of data from two Phase 3 studies (RAJ3 and RAJ4) of peficitinib (100 and 150 mg/day) in Asian rheumatoid arthritis patients investigated clinical disease activity index (CDAI) remission and low disease activity rates from baseline to Week 52. CDAI, Health Assessment Questionnaire-Disability Index, and van der Heijde-modified total Sharp score remission/low disease activity rates at Week 52 were evaluated among patients achieving CDAI remission at Weeks 12/28. Logistic regression analyses explored the relationship between baseline characteristics and CDAI remission/low disease activity rates. RESULTS CDAI remission rates increased over time in a dose-dependent manner in both peficitinib-treated groups. Most patients achieving CDAI remission at Weeks 12/28 also achieved remission at Week 52. Following the multivariate analysis of demographic and baseline characteristics, factors associated with the achievement of CDAI remission at Week 28 included male sex, low baseline prednisone dose (RAJ3 only), and low baseline Disease Activity Score 28-C-reactive protein (RAJ4 only). CONCLUSIONS Peficitinib demonstrated persistent efficacy in clinical remission to Week 52. Baseline characteristics associated with CDAI remission were mostly consistent with previous studies using other disease-modifying antirheumatic drugs.
-
2.
[ 18 F]-PSMA-1007 PET imaging optimization and inter-rater reliability - a comparison of three different reconstructions read by four radiologists.
Jonmarker, O, Nilsson, T, Axelsson, R, Ericson, LH, Tran, TA, Tzortzakakis, A, Savitcheva, I, Holstensson, M
Nuclear medicine communications. 2024;(5):389-395
Abstract
OBJECTIVES To increase understanding of optimal imaging parameters [ 18 F]PSMA-1007 when imaging patients with prostate cancer and to determine interrater agreement using [ 18 F]PSMA-1007. METHODS In this observational study, four independent physicians read reconstruction sets using bedtimes of 1, 2 and 3 minutes of patients undergoing [ 18 F]PSMA-1007. positron emission topography. Clear and equivocal lesions and their locations were recorded. Image noise was rated on a four-point scale. Lesion counts were compared using inter-class correlation whereas noise ratings were compared using generalized estimating equations. Repeated cases were used to assess intra-rater agreement. RESULTS Sixty reconstruction sets of 16 consecutively examined participants were included. Participants had a mean age of 71.5 years, six of them were examined prior to any treatment, three had a history of radiotherapy and seven of prostatectomy. Median Gleason score of primary tumors was 7. Imaging was performed after a mean of 132 min using a mean 3.95 MBq/Kg body weight of [ 18 F] PSMA-1007. Neither the total number of lesions per location nor the proportion of equivocal lesions varied consistently between bedtimes. Inter-rater reliability scores varied depending on location from 0.40 to 1.0 and were similar for all bedtimes. Intra-rater reliability varied between 0.70 and 0.76 for the three different bedtimes. Noise ratings were significantly lower for 1 minute than 3 minutes per bed. CONCLUSION In the setting of [ 18 F]PSMA-1007 PET CT, 1, 2 and 3 minutes per bed produce similar results unlikely to affect clinical interpretation. Image noise ratings favor 2 and 3 minutes per bed.
-
3.
A randomized placebo-controlled trial of nicotinamide riboside in older adults with mild cognitive impairment.
Orr, ME, Kotkowski, E, Ramirez, P, Bair-Kelps, D, Liu, Q, Brenner, C, Schmidt, MS, Fox, PT, Larbi, A, Tan, C, et al
GeroScience. 2024;(1):665-682
-
-
Free full text
-
Abstract
Nicotinamide riboside (NR) increases blood levels of NAD+, a cofactor central to energy metabolism, and improves brain function in some rodent models of neurodegeneration. We conducted a placebo-controlled randomized pilot study with the primary objective of determining safety of NR in older adults with mild cognitive impairment (MCI). Twenty subjects with MCI were randomized to receive placebo or NR using dose escalation to achieve, and maintain, a final dose of 1 g/day over a 10-week study duration. The primary outcome was post-treatment change from baseline measures of cognition (Montreal Cognitive Assessment, MoCA). Predefined secondary outcomes included post-treatment changes in cerebral blood flow (CBF); blood NAD+ levels; and additional neurocognitive, psychometric, and physical performance tests. DNA methylation was assessed in peripheral blood mononuclear cells (PBMCs) as an exploratory outcome. The target NR dose was safely achieved as evidenced by a 2.6-fold increase in blood NAD+ in the NR group (p < 0.001, 95% CI [17.77, 43.49]) with no between-group difference in adverse event reporting. MoCA and other neurocognitive and psychometric metrics remained stable throughout the study. NR reduced CBF in the default mode network (DMN) with greatest differences observed in the left inferior parietal lobe (IPL) (DMN p = 0.013, μ = 0.92, 95% CI [0.23, 1.62]; left IPL p = 0.009, μ = 1.66, 95% CI [0.5, 2.82]). Walking speed in the placebo group significantly improved across the study duration suggestive of a practice effect but did not change in the NR group (p = 0.0402 and p = 0.4698, respectively). Other secondary outcome measures remained stable. Global methylation analyses indicated a modest NR-associated increase in DNA methylation and concomitant reduction in epigenetic age as measured by PhenoAge and GrimAge epigenetic clock analyses. In summary, NR significantly increased blood NAD+ concentrations in older adults with MCI. NR was well tolerated and did not alter cognition. While CBF was reduced by NR treatment, statistical significance would not have withstood multiple comparisons correction. A larger trial of longer duration is needed to determine the potential of NR as a strategy to improve cognition and alter CBF in older adults with MCI. ClinicalTrials.gov NCT02942888.
-
4.
The NAD+ Precursor Nicotinamide Riboside Rescues Mitochondrial Defects and Neuronal Loss in iPSC derived Cortical Organoid of Alpers' Disease.
Hong, Y, Zhang, Z, Yangzom, T, Chen, A, Lundberg, BC, Fang, EF, Siller, R, Sullivan, GJ, Zeman, J, Tzoulis, C, et al
International journal of biological sciences. 2024;(4):1194-1217
Abstract
Alpers' syndrome is an early-onset neurodegenerative disorder usually caused by biallelic pathogenic variants in the gene encoding the catalytic subunit of polymerase-gamma (POLG), which is essential for mitochondrial DNA (mtDNA) replication. The disease is progressive, incurable, and inevitably it leads to death from drug-resistant status epilepticus. The neurological features of Alpers' syndrome are intractable epilepsy and developmental regression, with no effective treatment; the underlying mechanisms are still elusive, partially due to lack of good experimental models. Here, we generated the patient derived induced pluripotent stem cells (iPSCs) from one Alpers' patient carrying the compound heterozygous mutations of A467T (c.1399G>A) and P589L (c.1766C>T), and further differentiated them into cortical organoids and neural stem cells (NSCs) for mechanistic studies of neural dysfunction in Alpers' syndrome. Patient cortical organoids exhibited a phenotype that faithfully replicated the molecular changes found in patient postmortem brain tissue, as evidenced by cortical neuronal loss and depletion of mtDNA and complex I (CI). Patient NSCs showed mitochondrial dysfunction leading to ROS overproduction and downregulation of the NADH pathway. More importantly, the NAD+ precursor nicotinamide riboside (NR) significantly ameliorated mitochondrial defects in patient brain organoids. Our findings demonstrate that the iPSC model and brain organoids are good in vitro models of Alpers' disease; this first-in-its-kind stem cell platform for Alpers' syndrome enables therapeutic exploration and has identified NR as a viable drug candidate for Alpers' disease and, potentially, other mitochondrial diseases with similar causes.
-
5.
Nicotinamide N-Methyltransferase in Acquisition of Stem Cell Properties and Therapy Resistance in Cancer.
Novak Kujundžić, R, Prpić, M, Đaković, N, Dabelić, N, Tomljanović, M, Mojzeš, A, Fröbe, A, Trošelj, KG
International journal of molecular sciences. 2021;(11)
Abstract
The activity of nicotinamide N-methyltransferase (NNMT) is tightly linked to the maintenance of the nicotinamide adenine dinucleotide (NAD+) level. This enzyme catalyzes methylation of nicotinamide (NAM) into methyl nicotinamide (MNAM), which is either excreted or further metabolized to N1-methyl-2-pyridone-5-carboxamide (2-PY) and H2O2. Enzymatic activity of NNMT is important for the prevention of NAM-mediated inhibition of NAD+-consuming enzymes poly-adenosine -diphosphate (ADP), ribose polymerases (PARPs), and sirtuins (SIRTs). Inappropriately high expression and activity of NNMT, commonly present in various types of cancer, has the potential to disrupt NAD+ homeostasis and cellular methylation potential. Largely overlooked, in the context of cancer, is the inhibitory effect of 2-PY on PARP-1 activity, which abrogates NNMT's positive effect on cellular NAD+ flux by stalling liberation of NAM and reducing NAD+ synthesis in the salvage pathway. This review describes, and discusses, the mechanisms by which NNMT promotes NAD+ depletion and epigenetic reprogramming, leading to the development of metabolic plasticity, evasion of a major tumor suppressive process of cellular senescence, and acquisition of stem cell properties. All these phenomena are related to therapy resistance and worse clinical outcomes.
-
6.
Creatine and Nicotinamide Prevent Oxidant-Induced Senescence in Human Fibroblasts.
Mahajan, AS, Arikatla, VS, Thyagarajan, A, Zhelay, T, Sahu, RP, Kemp, MG, Spandau, DF, Travers, JB
Nutrients. 2021;(11)
Abstract
Dermal fibroblasts provide structural support by producing collagen and other structural/support proteins beneath the epidermis. Fibroblasts also produce insulin-like growth factor-1 (IGF-1), which binds to the IGF-1 receptors (IGF-1Rs) on keratinocytes to activate signaling pathways that regulate cell proliferation and cellular responses to genotoxic stressors like ultraviolet B radiation. Our group has determined that the lack of IGF-1 expression due to fibroblast senescence in the dermis of geriatric individuals is correlated with an increased incidence of skin cancer. The present studies tested the hypothesis that pro-energetics creatine monohydrate (Cr) and nicotinamide (NAM) can protect normal dermal human fibroblasts (DHF) against experimentally induced senescence. To that end, we used an experimental model of senescence in which primary DHF are treated with hydrogen peroxide (H2O2) in vitro, with senescence measured by staining for beta-galactosidase activity, p21 protein expression, and senescence associated secretory phenotype cytokine mRNA levels. We also determined the effect of H2O2 on IGF-1 mRNA and protein expression. Our studies indicate that pretreatment with Cr or NAM protects DHF from the H2O2-induced cell senescence. Treatment with pro-energetics post-H2O2 had no effect. Moreover, these agents also inhibited reactive oxygen species generation from H2O2 treatment. These studies suggest a potential strategy for protecting fibroblasts in geriatric skin from undergoing stress-induced senescence, which may maintain IGF-1 levels and therefore limit carcinogenesis in epidermal keratinocytes.
-
7.
Long-Term Outcomes of Radical Radiation Therapy with Hypoxia Modification with Biomarker Discovery for Stratification: 10-Year Update of the BCON (Bladder Carbogen Nicotinamide) Phase 3 Randomized Trial (ISRCTN45938399).
Song, YP, Mistry, H, Irlam, J, Valentine, H, Yang, L, Lane, B, West, C, Choudhury, A, Hoskin, PJ
International journal of radiation oncology, biology, physics. 2021;(5):1407-1415
Abstract
PURPOSE Many muscle-invasive bladder cancers are hypoxic, which limits the efficacy of radiation therapy. Hypoxia modification using carbogen and nicotinamide has been tested in a phase 3 trial, Bladder Carbogen Nicotinamide. We present mature follow-up data with biomarker predictions of outcomes. METHODS AND MATERIALS Bladder Carbogen Nicotinamide is a prospective, phase 3, multicenter, randomized, 2-arm, nonblinded clinical trial. Participants were randomized to receive radical radiation therapy (RT; control arm) alone or with the addition of carbogen (98% O2; 2% CO2) and nicotinamide (CON). Patients with muscle-invasive or high-grade non-muscle invasive bladder cancer were included. Tumor tissue was collected at entry and was analyzed for tumor necrosis, hypoxia (24-gene signature), and basal and luminal tumor molecular subtypes. Overall survival (OS) and disease-free survival and relationships with biomarker status outcomes are analyzed using multivariable Cox regression and log-rank analysis. RESULTS We analyzed 333 patients with a median follow-up of 10.3 years. The 10-year OS rates were 30% (95% confidence interval [CI], 0.23-0.39) in RT + CON patients and 24% (95% CI, 0.18-0.33) in the RT-alone patients (hazard ratio [HR], 0.80; 95% CI, 0.61-1.04; P = .08). The greatest benefit from CON was seen in patients with tumor necrosis (n = 79; 5-year OS, 53% vs. 33% in patients without tumor necrosis; HR, 0.59; 95% CI, 0.36-0.99; P = .04). Cases with a high hypoxia gene score (n = 75) had a 5-year OS rate of 51%, compared to 34% for a low score (HR, 0.64; 95% CI, 0.38-1.08; P = .09); those with the basal molecular subtype (n = 70) had a 5-year OS rate of 58%, compared to 38% for those with the luminal subtype (HR, 0.58; 95% CI, 0.32-1.06; P = .08). CONCLUSIONS Although the improvement in long-term OS in the whole population is not statistically significant, patients selected by necrosis and high hypoxia gene score benefitted from hypoxia modification.
-
8.
Cognitive Outcomes at 18 Months: Findings from the Early Life Interventions for Childhood Growth and Development in Tanzania (ELICIT) Trial.
Parpia, T, Svensen, E, Elwood, S, Wanjuhi, A, Blacy, L, Bayo, E, Houpt, E, Rogawski McQuade, E, DeBoer, M, Platts-Mills, J, et al
The American journal of tropical medicine and hygiene. 2021;(2):441-445
-
-
Free full text
-
Abstract
Micronutrient deficiencies and enteric infections negatively impact child growth and development. We enrolled children shortly after birth in a randomized, placebo-controlled, 2 × 2 factorial interventional trial in Haydom, Tanzania, to assess nicotinamide and/or antimicrobials (azithromycin and nitazoxanide) effect on length at 18 months of age. Cognitive score at 18 months using the Malawi Developmental Assessment Tool (MDAT), which includes gross motor, fine motor, language, and social assessments, was a secondary outcome. Here, we present the MDAT results of 1,032 children. There was no effect of nicotinamide (change in development-for-age Z score [DAZ] -0.08; 95% CI: -0.16, 0) or antimicrobials (change in DAZ 0.04; 95% CI: -0.06, 0.13) on overall MDAT score. The interventions had no effect on cognitive outcomes in subgroups defined by gender, socioeconomic status, birthweight, and birth season or on MDAT subscores. Further analyses are needed to identify targetable risk factors for impaired cognitive development in these settings.
-
9.
Nicotinamide for Keratinocyte Carcinoma Chemoprevention: A Nationwide Survey of Mohs Surgeons.
Desai, S, Olbricht, S, Ruiz, ES, Hartman, RI
Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.]. 2021;(4):452-453
Abstract
BACKGROUND Nicotinamide has been shown to reduce keratinocyte carcinoma (KC) in high-risk patients in a randomized controlled trial setting. Data on nicotinamide's use for KC prevention are limited. OBJECTIVE To characterize nicotinamide prescribing patterns among Mohs surgeons. METHODS AND MATERIALS We surveyed 1,500 members of the American College of Mohs Surgeons regarding their demographics, use of nicotinamide, and safety perceptions. We performed multiple logistic regression analysis to evaluate correlations between physician characteristics and nicotinamide prescribing habits. RESULTS 76.9% of survey respondents recommend nicotinamide for KC prevention. Twenty percent of respondents have recommended nicotinamide to more than 100 patients in the past year. Forty-five percent of respondents report a duration of use of 2 years or more in their patients. 63.8% of respondents had no concerns over nicotinamide's safety with long-term use. Individuals who answered "yes," "maybe," or "uncertain" to having safety concerns over long-term nicotinamide use and individuals in practice for more than 10 years were less likely (odds ratio [OR] 0.30, 95% confidence interval [CI] 0.13-0.71 and OR 0.20, 95% CI 0.05, 0.82, respectively) to have recommended nicotinamide to patients for KC prevention. CONCLUSION Given the widespread nicotinamide use among Mohs surgeons, additional studies on nicotinamide cost-effectiveness, safety, and use patterns are needed.
-
10.
The Role of Nicotinamide in Cancer Chemoprevention and Therapy.
Nikas, IP, Paschou, SA, Ryu, HS
Biomolecules. 2020;(3)
Abstract
Nicotinamide (NAM) is a water-soluble form of Vitamin B3 (niacin) and a precursor of nicotinamide-adenine dinucleotide (NAD+) which regulates cellular energy metabolism. Except for its role in the production of adenosine triphosphate (ATP), NAD+ acts as a substrate for several enzymes including sirtuin 1 (SIRT1) and poly ADP-ribose polymerase 1 (PARP1). Notably, NAM is an inhibitor of both SIRT1 and PARP1. Accumulating evidence suggests that NAM plays a role in cancer prevention and therapy. Phase III clinical trials have confirmed its clinical efficacy for non-melanoma skin cancer chemoprevention or as an adjunct to radiotherapy against head and neck, laryngeal, and urinary bladder cancers. Evidence for other cancers has mostly been collected through preclinical research and, in its majority, is not yet evidence-based. NAM has potential as a safe, well-tolerated, and cost-effective agent to be used in cancer chemoprevention and therapy. However, more preclinical studies and clinical trials are needed to fully unravel its value.