Using metabolic screening, Allen et al. identify an adenosine to inosine deamination defect in astrocytes from ALS patients. This defect is the result of reduced expression of adenosine deaminase, ...leading to increased susceptibility to adenosine-mediated toxicity. Astrocyte inosine supplementation reverses the motor neuron toxicity observed with patient astrocytes in co-culture.
Abstract
As clinical evidence supports a negative impact of dysfunctional energy metabolism on the disease progression in amyotrophic lateral sclerosis, it is vital to understand how the energy metabolic pathways are altered and whether they can be restored to slow disease progression. Possible approaches include increasing or rerouting catabolism of alternative fuel sources to supplement the glycolytic and mitochondrial pathways such as glycogen, ketone bodies and nucleosides. To analyse the basis of the catabolic defect in amyotrophic lateral sclerosis we used a novel phenotypic metabolic array. We profiled fibroblasts and induced neuronal progenitor-derived human induced astrocytes from C9orf72 amyotrophic lateral sclerosis patients compared to normal controls, measuring the rates of production of reduced nicotinamide adenine dinucleotides from 91 potential energy substrates. This approach shows for the first time that C9orf72 human induced astrocytes and fibroblasts have an adenosine to inosine deamination defect caused by reduction of adenosine deaminase, which is also observed in induced astrocytes from sporadic patients. Patient-derived induced astrocyte lines were more susceptible to adenosine-induced toxicity, which could be mimicked by inhibiting adenosine deaminase in control lines. Furthermore, adenosine deaminase inhibition in control induced astrocytes led to increased motor neuron toxicity in co-cultures, similar to the levels observed with patient derived induced astrocytes. Bypassing metabolically the adenosine deaminase defect by inosine supplementation was beneficial bioenergetically in vitro, increasing glycolytic energy output and leading to an increase in motor neuron survival in co-cultures with induced astrocytes. Inosine supplementation, in combination with modulation of the level of adenosine deaminase may represent a beneficial therapeutic approach to evaluate in patients with amyotrophic lateral sclerosis.
Abstract Gemtuzumab ozogamicin (GO) was approved for marketing in 2000 by the United States Food and Drug Administration (FDA) for older patients with relapsed acute myeloid leukemia (AML). Four ...months later, 14 phase II clinical trial participants who received novel GO-containing combination chemotherapy regimens developed an unexpected hepatic toxicity termed sinusoidal obstructive syndrome (SOS) or hepatic veno-occlusive disease (VOD). Investigators associated with the Research on Adverse Drug Events and Reports (RADAR) project reviewed safety reports for GO included in reports of clinical trials and observational studies, interim reports from an FDA mandated Prospective Observational Registry, and the Food and Drug Administration's Adverse Event Reporting System. Medline searches provided incidence estimates of GO-associated SOS and comparative rates of SOS without GO. SOS is characterized by hyperbilirubinemia, painful hepatomegaly, ascites, and sudden weight gain developing at a median of 10 days following GO administration for patients who did not undergo an allogeneic SCT procedure and 13 days following an allogeneic SCT for patients who had previously received GO. Among adult AML patients who received GO in clinical trials, SOS incidence was 3% at doses ≤6 mg/m2 if administered as monotherapy or in combination with non-hepatotoxic agents versus 28% if administered with thioguanine and 15% when administered as monotherapy at a dose of 9 mg/m2 . Observational studies identified SOS rates between 15% and 40% if an SCT is performed within 3 months of GO administration. The FDA mandated Prospective Observational Registry of patients who receive care at 60 medical centers has identified GO-associated SOS rates of 14% if an SCT is performed and 9% otherwise. Caution is advised when administering GO in routine clinical practice, particularly if administered with other hepatotoxic agents, at doses and schedules more intensive than those approved by the FDA, or within 3 months of a SCT procedure.
Squamous intraepithelial lesion is an abnormal growth of epithelial cells on the surface of the cervix that may lead to cervical cancer. Analytical protocols for the determination of squamous ...intraepithelial lesions are in high demand, since cervical cancer is the fourth most diagnosed cancer among women in the world. Here, paper spray ionization mass spectrometry (PSI-MS) is used to distinguish between healthy (negative for intraepithelial lesion or malignancy) and diseased (high-grade squamous intraepithelial lesion) blood plasmas. A total of 86 blood samples of different women (49 healthy samples, 37 diseased samples) were collected, and the plasmas were prepared. Then, 10 μL of each plasma sample was deposited onto triangular papers for PSI-MS analysis. No additional step of sample preparation was necessary. The interval-successive projection algorithm linear discriminant analysis (iSPA-LDA) was applied to the PSI mass spectra, showing six ions (mostly phospholipids) that were predictive of healthy and diseased plasmas. Values of 77% accuracy, 86% sensitivity, 80% positive predictive value (PPV), and 75% negative predictive value (NPV) were achieved. This study provides evidence that PSI-MS may potentially be used as a fast and simple analytical technique for the early diagnosis of cervical cancer.
Enzalutamide and lutetium-177 177LuLu-prostate-specific membrane antigen (PSMA)-617 both improve overall survival in patients with metastatic castration-resistant prostate cancer. Androgen and PSMA ...receptors have a close intracellular relationship, with data suggesting complementary benefit if targeted concurrently. In this study, we assessed the activity and safety of enzalutamide plus adaptive-dosed 177LuLu-PSMA-617 versus enzalutamide alone as first-line treatment for metastatic castration-resistant prostate cancer.
ENZA-p was an open-label, randomised, controlled phase 2 trial done at 15 hospitals in Australia. Participants were men aged 18 years or older with metastatic castration-resistant prostate cancer not previously treated with docetaxel or androgen receptor pathway inhibitors for metastatic castration-resistant prostate cancer, gallium-68 68GaGa-PSMA-PET-CT (PSMA-PET-CT) positive disease, Eastern Cooperative Oncology Group performance status of 0–2, and at least two risk factors for early progression on enzalutamide. Participants were randomly assigned (1:1) by a centralised, web-based system using minimisation with a random component to stratify for study site, disease burden, use of early docetaxel, and previous treatment with abiraterone acetate. Patients were either given oral enzalutamide 160 mg daily alone or with adaptive-dosed (two or four doses) intravenous 7·5 GBq 177LuLu-PSMA-617 every 6–8 weeks dependent on an interim PSMA-PET-CT (week 12). The primary endpoint was prostate-specific antigen (PSA) progression-free survival, defined as the interval from the date of randomisation to the date of first evidence of PSA progression, commencement of non-protocol anticancer therapy, or death. The analysis was done in the intention-to-treat population, using stratified Cox proportional hazards regression. This trial is registered with ClinicalTrials.gov, NCT04419402, and participant follow-up is ongoing.
162 participants were randomly assigned between Aug 17, 2020, and July 26, 2022. 83 men were assigned to the enzalutamide plus 177LuLu-PSMA-617 group, and 79 were assigned to the enzalutamide group. Median follow-up in this interim analysis was 20 months (IQR 18–21), with 32 (39%) of 83 patients in the enzalutamide plus 177LuLu-PSMA-617 group and 16 (20%) of 79 patients in the enzalutamide group remaining on treatment at the data cutoff date. Median age was 71 years (IQR 64–76). Median PSA progression-free survival was 13·0 months (95% CI 11·0–17·0) in the enzalutamide plus 177LuLu-PSMA-617 group and 7·8 months (95% CI 4·3–11·0) in the enzalutamide group (hazard ratio 0·43, 95% CI 0·29–0·63, p<0·0001). The most common adverse events (all grades) were fatigue (61 75% of 81 patients), nausea (38 47%), and dry mouth (32 40%) in the enzalutamide plus 177LuLu-PSMA-617 group and fatigue (55 70% of 79), nausea (21 27%), and constipation (18 23%) in the enzalutamide group. Grade 3–5 adverse events occurred in 32 (40%) of 81 patients in the enzalutamide plus 177LuLu-PSMA-617 group and 32 (41%) of 79 patients in the enzalutamide group. Grade 3 events that occurred only in the enzalutamide plus 177LuLu-PSMA-617 group included anaemia (three 4% of 81 participants) and decreased platelet count (one 1% participant). No grade 4 or 5 events were attributed to treatment on central review in either group.
The addition of 177LuLu-PSMA-617 to enzalutamide improved PSA progression-free survival providing evidence of enhanced anticancer activity in patients with metastatic castration-resistant prostate cancer with risk factors for early progression on enzalutamide and warrants further evaluation of the combination more broadly in metastatic prostate cancer.
Prostate Cancer Research Alliance (Movember and Australian Federal Government), St Vincent's Clinic Foundation, GenesisCare, Roy Morgan Research, and Endocyte (a Novartis company).
The International Society of Blood Transfusion Working Party on red cell immunogenetics and blood group terminology convened during the International congress in Cancun, July 2012. This report ...details the newly identified antigens in existing blood group systems and presents three new blood group systems.
The clinically important MAM blood group antigen is present on haematopoietic cells of all humans except rare MAM-negative individuals. Its molecular basis is unknown. By whole-exome sequencing we ...identify EMP3, encoding epithelial membrane protein 3 (EMP3), as a candidate gene, then demonstrate inactivating mutations in ten known MAM-negative individuals. We show that EMP3, a purported tumour suppressor in various solid tumours, is expressed in erythroid cells. Disruption of EMP3 by CRISPR/Cas9 gene editing in an immortalised human erythroid cell line (BEL-A2) abolishes MAM expression. We find EMP3 to associate with, and stabilise, CD44 in the plasma membrane. Furthermore, cultured erythroid progenitor cells from MAM-negative individuals show markedly increased proliferation and higher reticulocyte yields, suggesting an important regulatory role for EMP3 in erythropoiesis and control of cell production. Our data establish MAM as a new blood group system and demonstrate an interaction of EMP3 with the cell surface signalling molecule CD44.
Use of data mining at the Food and Drug Administration Duggirala, Hesha J; Tonning, Joseph M; Smith, Ella ...
Journal of the American Medical Informatics Association : JAMIA,
03/2016, Letnik:
23, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Objectives This article summarizes past and current data mining activities at the United States Food and Drug Administration (FDA).
Target audience We address data miners in all sectors, anyone ...interested in the safety of products regulated by the FDA (predominantly medical products, food, veterinary products and nutrition, and tobacco products), and those interested in FDA activities.
Scope Topics include routine and developmental data mining activities, short descriptions of mined FDA data, advantages and challenges of data mining at the FDA, and future directions of data mining at the FDA.
Despite the pivotal role of jasmonic acid in the outcome of plant-microorganism interactions, JA-signaling components in roots of perennial trees like western balsam poplar (Populus trichocarpa) are ...poorly characterized. Here we decipher the poplar-root JA-perception complex centered on PtJAZ6, a co-repressor of JA-signaling targeted by the effector protein MiSSP7 from the ectomycorrhizal basidiomycete Laccaria bicolor during symbiotic development. Through protein-protein interaction studies in yeast we determined the poplar root proteins interacting with PtJAZ6. Moreover, we assessed via yeast triple-hybrid how the mutualistic effector MiSSP7 reshapes the association between PtJAZ6 and its partner proteins. In the absence of the symbiotic effector, PtJAZ6 interacts with the transcription factors PtMYC2s and PtJAM1.1. In addition, PtJAZ6 interacts with it-self and with other Populus JAZ proteins. Finally, MiSSP7 strengthens the binding of PtJAZ6 to PtMYC2.1 and antagonizes PtJAZ6 homo-/heterodimerization. We conclude that a symbiotic effector secreted by a mutualistic fungus may promote the symbiotic interaction through altered dynamics of a JA-signaling-associated protein-protein interaction network, maintaining the repression of PtMYC2.1-regulated genes.
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