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Journal of Cancer Research and Clinical... Jul 2024In patients with metastatic pancreatic cancer, after failure of gemcitabine/nab-paclitaxel, this trial compares the efficacy of second-line therapy with FOLFIRI vs. OFF... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
In patients with metastatic pancreatic cancer, after failure of gemcitabine/nab-paclitaxel, this trial compares the efficacy of second-line therapy with FOLFIRI vs. OFF (1:1 randomisation) with cross-over to the vice-versa regimen as third-line therapy.
PATIENTS AND METHODS
The primary endpoint was PFS (progression-free survival: time from randomization until progression or death) of second-line therapy. The trial aimed to demonstrate non-inferiority of FOLFIRI vs OFF (non-inferiority margin of a hazard ratio (HR) of 1.5, power of 80% and a significance level of 5%, 196 events needed). Secondary endpoints included overall survival (OS), progression-free survival of third-line therapy and safety. The trial is registered with EudraCT Nr. 2016-004640-11.
RESULTS
The trial was terminated with 60 evaluable (37 with FOLFIRI, 23 with OFF) patients due to insufficient recruitment. PFS of second-line therapy was 2.4 (95% CI 2.3-2.6) months with FOLFIRI vs 2.4 (95% CI 2.2-2.7) months with OFF (HR: 0.80, 95% CI 0.45-1.42, P = 0.43). OS was comparable between the arms (HR: 0.95, 95% CI 0.54-1.66), P = 0.84). Only 4 out of 28 (14%) patients receiving third-line therapy achieved a disease control (partial remission or stable disease). Both second-line regimens were well tolerated without new or unexpected safety signals being observed.
CONCLUSION
The exploratory analysis of this early terminated trial suggests that FOLFIRI and OFF have similar efficacy ant toxicity as second-line therapy of PDAC after failure of gemcitabine/nab-paclitaxel. Third-line therapy regardless of regimen does not provide satisfactory efficacy in this sequential treatment algorithm.
Topics: Humans; Pancreatic Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Male; Fluorouracil; Female; Middle Aged; Leucovorin; Aged; Oxaliplatin; Irinotecan; Adult; Camptothecin; Progression-Free Survival; Cross-Over Studies
PubMed: 38951245
DOI: 10.1007/s00432-024-05827-x -
Nature Communications Jun 2024Keratoconus, a disorder characterized by corneal thinning and weakening, results in vision loss. Corneal crosslinking (CXL) can halt the progression of keratoconus. The...
Keratoconus, a disorder characterized by corneal thinning and weakening, results in vision loss. Corneal crosslinking (CXL) can halt the progression of keratoconus. The development of accelerated corneal crosslinking (A-CXL) protocols to shorten the treatment time has been hampered by the rapid depletion of stromal oxygen when higher UVA intensities are used, resulting in a reduced cross-linking effect. It is therefore imperative to develop better methods to increase the oxygen concentration within the corneal stroma during the A-CXL process. Photocatalytic oxygen-generating nanomaterials are promising candidates to solve the hypoxia problem during A-CXL. Biocompatible graphitic carbon nitride (g-CN) quantum dots (QDs)-based oxygen self-sufficient platforms including g-CN QDs and riboflavin/g-CN QDs composites (RF@g-CN QDs) have been developed in this study. Both display excellent photocatalytic oxygen generation ability, high reactive oxygen species (ROS) yield, and excellent biosafety. More importantly, the A-CXL effect of the g-CN QDs or RF@g-CN QDs composite on male New Zealand white rabbits is better than that of the riboflavin 5'-phosphate sodium (RF) A-CXL protocol under the same conditions, indicating excellent strengthening of the cornea after A-CXL treatments. These lead us to suggest the potential application of g-CN QDs in A-CXL for corneal ectasias and other corneal diseases.
Topics: Quantum Dots; Animals; Graphite; Oxygen; Riboflavin; Rabbits; Male; Cross-Linking Reagents; Nitrogen Compounds; Reactive Oxygen Species; Keratoconus; Ultraviolet Rays; Cornea; Humans; Photosensitizing Agents; Corneal Stroma
PubMed: 38951161
DOI: 10.1038/s41467-024-49645-8 -
The Journal of Clinical Investigation Jun 2024Activating mutations of FLT3 contribute to deregulated hematopoietic stem and progenitor cell (HSC/Ps) growth and survival in patients with acute myeloid leukemia (AML),...
Activating mutations of FLT3 contribute to deregulated hematopoietic stem and progenitor cell (HSC/Ps) growth and survival in patients with acute myeloid leukemia (AML), leading to poor overall survival. AML patients treated with investigational drugs targeting mutant FLT3, including Quizartinib and Crenolanib, develop resistance to these drugs. Development of resistance is largely due to acquisition of cooccurring mutations and activation of additional survival pathways, as well as emergence of additional FLT3 mutations. Despite the high prevalence of FLT3 mutations and their clinical significance in AML, there are few targeted therapeutic options available. We have identified 2 novel nicotinamide-based FLT3 inhibitors (HSN608 and HSN748) that target FLT3 mutations at subnanomolar concentrations and are potently effective against drug-resistant secondary mutations of FLT3. These compounds show antileukemic activity against FLT3ITD in drug-resistant AML, relapsed/refractory AML, and in AML bearing a combination of epigenetic mutations of TET2 along with FLT3ITD. We demonstrate that HSN748 outperformed the FDA-approved FLT3 inhibitor Gilteritinib in terms of inhibitory activity against FLT3ITD in vivo.
Topics: Humans; Leukemia, Myeloid, Acute; fms-Like Tyrosine Kinase 3; Drug Resistance, Neoplasm; Animals; Mice; Niacinamide; Cell Line, Tumor; Xenograft Model Antitumor Assays; Female; Antineoplastic Agents; Mutation; Mice, SCID; Mice, Inbred NOD
PubMed: 38950330
DOI: 10.1172/JCI169245 -
Investigative Ophthalmology & Visual... Jul 2024Glucocorticoid-induced glaucoma (GIG) is a prevalent complication associated with glucocorticoids (GCs), resulting in irreversible blindness. GIG is characterized by the...
PURPOSE
Glucocorticoid-induced glaucoma (GIG) is a prevalent complication associated with glucocorticoids (GCs), resulting in irreversible blindness. GIG is characterized by the abnormal deposition of extracellular matrix (ECM) in the trabecular meshwork (TM), elevation of intraocular pressure (IOP), and loss of retinal ganglion cells (RGCs). The objective of this study is to investigate the effects of nicotinamide riboside (NR) on TM in GIG.
METHODS
Primary human TM cells (pHTMs) and C57BL/6J mice responsive to GCs were utilized to establish in vitro and in vivo GIG models, respectively. The study assessed the expression of ECM-related proteins in TM and the functions of pHTMs to reflect the effects of NR. Mitochondrial morphology and function were also examined in the GIG cell model. GIG progression was monitored through IOP, RGCs, and mitochondrial morphology. Intracellular nicotinamide adenine dinucleotide (NAD+) levels of pHTMs were enzymatically assayed.
RESULTS
NR significantly prevented the expression of ECM-related proteins and alleviated dysfunction in pHTMs after dexamethasone treatment. Importantly, NR protected damaged ATP synthesis, preventing overexpression of mitochondrial reactive oxygen species (ROS), and also protect against decreased mitochondrial membrane potential induced by GCs in vitro. In the GIG mouse model, NR partially prevented the elevation of IOP and the loss of RGCs. Furthermore, NR effectively suppressed the excessive expression of ECM-associated proteins and mitigated mitochondrial damage in vivo.
CONCLUSIONS
Based on the results, NR effectively enhances intracellular levels of NAD+, thereby mitigating abnormal ECM deposition and TM dysfunction in GIG by attenuating mitochondrial damage induced by GCs. Thus, NR has promising potential as a therapeutic candidate for GIG treatment.
Topics: Animals; Niacinamide; Pyridinium Compounds; Glucocorticoids; Mice, Inbred C57BL; Mitochondria; Mice; Glaucoma; Extracellular Matrix; Intraocular Pressure; Humans; Disease Models, Animal; Trabecular Meshwork; Cells, Cultured; Retinal Ganglion Cells; Reactive Oxygen Species; Dexamethasone; Male
PubMed: 38949632
DOI: 10.1167/iovs.65.8.1 -
The Journals of Gerontology. Series A,... Aug 2024
Topics: Humans; Folic Acid; Dementia; Vitamin B Complex; Dietary Supplements; Brain; Aged; Risk Factors
PubMed: 38949211
DOI: 10.1093/gerona/glae123 -
Physiological Reports Jul 2024Cancer cachexia is a multifactorial syndrome associated with advanced cancer that contributes to mortality. Cachexia is characterized by loss of body weight and muscle...
Cancer cachexia is a multifactorial syndrome associated with advanced cancer that contributes to mortality. Cachexia is characterized by loss of body weight and muscle atrophy. Increased skeletal muscle mitochondrial reactive oxygen species (ROS) is a contributing factor to loss of muscle mass in cachectic patients. Mice inoculated with Lewis lung carcinoma (LLC) cells lose weight, muscle mass, and have lower muscle sirtuin-1 (sirt1) expression. Nicotinic acid (NA) is a precursor to nicotinamide dinucleotide (NAD+) which is exhausted in cachectic muscle and is a direct activator of sirt1. Mice lost body and muscle weight and exhibited reduced skeletal muscle sirt1 expression after inoculation with LLC cells. C2C12 myotubes treated with LLC-conditioned media (LCM) had lower myotube diameter. We treated C2C12 myotubes with LCM for 24 h with or without NA for 24 h. C2C12 myotubes treated with NA maintained myotube diameter, sirt1 expression, and had lower mitochondrial superoxide. We then used a sirt1-specific small molecule activator SRT1720 to increase sirt1 activity. C2C12 myotubes treated with SRT1720 maintained myotube diameter, prevented loss of sirt1 expression, and attenuated mitochondrial superoxide production. Our data provides evidence that NA may be beneficial in combating cancer cachexia by maintaining sirt1 expression and decreasing mitochondrial superoxide production.
Topics: Animals; Cachexia; Sirtuin 1; Muscle Fibers, Skeletal; Mice; Oxidative Stress; Mice, Inbred C57BL; Carcinoma, Lewis Lung; Male; Heterocyclic Compounds, 4 or More Rings; Mitochondria, Muscle; Cell Line; Niacin; Mitochondria; Reactive Oxygen Species
PubMed: 38946587
DOI: 10.14814/phy2.16103 -
Journal of Nutritional Science and... 2024Pyridoxamine (PM) is one of the natural vitamins B6 (VB6) and functions as an endogenous inhibitor for the formation of AGEs (advanced glycation end products). The AGEs...
Pyridoxamine (PM) is one of the natural vitamins B6 (VB6) and functions as an endogenous inhibitor for the formation of AGEs (advanced glycation end products). The AGEs are implicated in aging, diabetes, and various neuropsychiatric disease, including schizophrenia, Alzheimer's disease, and Parkinson's disease. However, it is unclear whether the absence of PM per se accumulates AGEs in vivo and causes behavioral dysfunctions. To address these points, we raised PM-deficient fruit flies, Drosophila melanogaster, with the sterilized defined medium. Flies reared in a PM-deficient medium accumulated AGEs and reduced lifespan, impaired gustatory response, sleep, courtship behavior, and olfactory learning. These results suggest that PM suppresses AGE accumulation in vivo and is required for regulating innate and empirical behaviors.
Topics: Animals; Drosophila melanogaster; Glycation End Products, Advanced; Pyridoxamine; Behavior, Animal; Longevity; Male; Sleep; Female; Sexual Behavior, Animal; Learning
PubMed: 38945891
DOI: 10.3177/jnsv.70.252 -
Journal of Nutritional Science and... 2024Niacin is a cofactor in many biological reactions related to energy metabolism, redox reactions, DNA repair and longevity. Although it has been considered that...
Niacin is a cofactor in many biological reactions related to energy metabolism, redox reactions, DNA repair and longevity. Although it has been considered that increasing energy expenditure increases NAD consumption, little study has directly demonstrated the effect of exercise on niacin nutritional status. We have recently established the niacin insufficient model mice using kynurenine 3-monooxygenase knock out (KMO) mice with niacin-limited diet, which lack the de novo NAD synthesis pathway from tryptophan. To evaluate the effects of chronic endurance exercise on niacin nutritional status, 4 wk old KMO mice were fed 4 or 30 mg/kg nicotinic acid containing diets, and forced to swim in a running water pool every other day for 35 d. The swim-exercised mice fed 4 mg/kg nicotinic acid diet showed lower body weight gain and niacin nutritional markers such as liver and blood NAD, and urine nicotinamide metabolites than the sedentary mice. These animals did not show any difference in the NAD synthesis, NAD salvage and nicotinamide catabolic pathways. Chronic endurance exercise failed to affect any indices in the mice fed the 30 mg/kg nicotinic acid diet. When the diet was exchanged the 4 mg/kg for 30 mg/kg nicotinic acid diet to the mice showed chronic endurance exercise-induced growth retardation, their body weight rapidly increased. These results show that chronic endurance exercise impairs niacin nutritional status in the niacin insufficient mice, and enough niacin intake can prevent this impairment. Our findings also suggest that chronic endurance exercise increases niacin requirement by increase of NAD consumption.
Topics: Animals; Niacin; Nutritional Status; Physical Conditioning, Animal; Male; Mice; Mice, Knockout; Physical Endurance; Liver; NAD; Swimming; Weight Gain; Diet; Body Weight; Mice, Inbred C57BL; Niacinamide
PubMed: 38945883
DOI: 10.3177/jnsv.70.185 -
Physiologia Plantarum 2024Maize (Zea mays L.) is an important food crop with a wide range of uses in both industry and agriculture. Drought stress during its growth cycle can greatly reduce maize...
Maize (Zea mays L.) is an important food crop with a wide range of uses in both industry and agriculture. Drought stress during its growth cycle can greatly reduce maize crop yield and quality. However, the molecular mechanisms underlying maize responses to drought stress remain unclear. In this work, a WRKY transcription factor-encoding gene, ZmWRKY30, from drought-treated maize leaves was screened out and characterized. ZmWRKY30 gene expression was induced by dehydration treatments. The ZmWRKY30 protein localized to the nucleus and displayed transactivation activity in yeast. Compared with wild-type (WT) plants, Arabidopsis lines overexpressing ZmWRKY30 exhibited a significantly enhanced drought stress tolerance, as evidenced by the improved survival rate, increased antioxidant enzyme activity by superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT), elevated proline content, and reduced lipid peroxidation recorded after drought stress treatment. In contrast, the mutator (Mu)-interrupted ZmWRKY30 homozygous mutant (zmwrky30) was more sensitive to drought stress than its null segregant (NS), characterized by the decreased survival rate, reduced antioxidant enzyme activity (SOD, POD, and CAT) and proline content, as well as increased malondialdehyde accumulation. RNA-Seq analysis further revealed that, under drought conditions, the knockout of the ZmWRKY30 gene in maize affected the expression of genes involved in reactive oxygen species (ROS), proline, and myo-inositol metabolism. Meanwhile, the zmwrky30 mutant exhibited significant downregulation of myo-inositol content in leaves under drought stress. Combined, our results suggest that ZmWRKY30 positively regulates maize responses to water scarcity. This work provides potential target genes for the breeding of drought-tolerant maize.
Topics: Zea mays; Reactive Oxygen Species; Droughts; Plant Proteins; Gene Expression Regulation, Plant; Homeostasis; Inositol; Transcription Factors; Arabidopsis; Plants, Genetically Modified; Stress, Physiological; Antioxidants; Plant Leaves; Drought Resistance
PubMed: 38945803
DOI: 10.1111/ppl.14423 -
The Journal of Dermatological Treatment Dec 2024Bullous pemphigoid induced by secukinumab in treatment of psoriasis is rare. We report a 49-year-old man with psoriasis who developed bullous pemphigoid during...
Bullous pemphigoid induced by secukinumab in treatment of psoriasis is rare. We report a 49-year-old man with psoriasis who developed bullous pemphigoid during treatment with secukinumab. Scattered tense vesicles with itching appeared all over the body after the fourth treatment. Bullous pemphigoid was confirmed by pathological examination and direct immunofluorescence. The patient was treated with topical corticosteroids, oral nicotinamide and minocycline hydrochloride. The lesions of bullous pemphigoid improved significantly after 7 days of treatment. Bullous pemphigoid is a rare adverse event following administration of secukinumab.
Topics: Humans; Pemphigoid, Bullous; Male; Middle Aged; Antibodies, Monoclonal, Humanized; Psoriasis; Minocycline; Niacinamide; Dermatologic Agents; Treatment Outcome
PubMed: 38945532
DOI: 10.1080/09546634.2024.2366535