ID: h-cb833ed8
Hypothesis
Senescence-Activated NAD+ Depletion Rescue
Senescence-Activated NAD+ Depletion Rescue starts from the claim that modulating CD38/NAMPT within the disease context of neurodegeneration can redirect a disease-relevant process.
EvidencePending (0%)📖 35 cit🗣 2 debates✓ 13 support✗ 10 oppose
✓ All Quality Gates Passed
🧪 Overview
Mechanistic Overview
Senescence-Activated NAD+ Depletion Rescue starts from the claim that modulating CD38/NAMPT within the disease context of neurodegeneration can redirect a disease-relevant process. The original description reads: "Molecular Mechanism and Rationale The senescence-activated NAD+ depletion hypothesis centers on the enzymatic activity of CD38, a multifunctional ectoenzyme that functions as the primary NAD+ glycohydrolase in mammalian tissues. CD38 exhibits dual enzymatic activities: it catalyzes the hydrolysis of NAD+ to adenosine diphosphoribose (ADPR) and nicotinamide, while also synthesizing cyclic ADPR (cADP-ribose), a potent calcium-mobilizing second messenger. In the context of neurodegeneration, senescent glial cells—particularly microglia and astrocytes—dramatically upregulate CD38 expression as part of the senescence-associated secretory phenotype (SASP). This upregulation creates discrete microdomains of NAD+ depletion surrounding senescent cells, establishing metabolic "dead zones" that compromise the bioenergetic integrity of neighboring neurons....
🧬 Mechanism
🧬 Curated Mechanism Pathway
Curated pathway from expert analysis
graph TD
A["DNA damage and<br/>oxidative stress<br/>triggers"] -->|"activates"| B["p53/p21 and<br/>p16INK4a/Rb<br/>senescence pathways"]
B -->|"induces"| C["Glial cell senescence<br/>(microglia and astrocytes)"]
C -->|"activates"| D["Senescence-Associated<br/>Secretory Phenotype<br/>(SASP)"]
D -->|"upregulates"| E["NF-kappaB and<br/>C/EBP-beta<br/>transcription factors"]
E -->|"transcriptionally<br/>activates"| F["CD38 expression<br/>(10-20 fold increase)"]
F -->|"produces"| G["CD38 NAD+<br/>glycohydrolase<br/>enzyme activity"]
G -->|"catalyzes"| H["NAD+ hydrolysis to<br/>ADPR and<br/>nicotinamide"]
G -->|"synthesizes"| I["Cyclic ADPR<br/>(cADP-ribose)<br/>second messenger"]
H -->|"creates"| J["Extracellular and<br/>cytosolic NAD+<br/>depletion zones"]
J -->|"establishes"| K["Metabolic dead zones<br/>(50-100 micrometer<br/>radius)"]
I -->|"mobilizes"| L["Intracellular<br/>calcium release<br/>signaling"]
K -->|"compromises"| M["Neuronal<br/>bioenergetic<br/>integrity"]
N["NAMPT salvage<br/>pathway enzyme<br/>activity"] -->|"competes with"| H
N -->|"attempts"| O["NAD+ biosynthesis<br/>from nicotinamide<br/>recycling"]
O -->|"insufficient<br/>capacity"| J
M -->|"leads to"| P["Mitochondrial<br/>dysfunction and<br/>ATP depletion"]
L -->|"contributes to"| P
P -->|"triggers"| Q["Neuronal death<br/>and synaptic<br/>dysfunction"]
Q -->|"manifests as"| R["Progressive<br/>neurodegeneration<br/>phenotype"]
S["CD38 inhibitors<br/>and NAMPT<br/>activators"] -->|"therapeutic<br/>intervention"| G
S -->|"restores"| T["NAD+ homeostasis<br/>and neuronal<br/>survival"]
classDef normal fill:#4fc3f7,stroke:#2196f3,color:#0d0d1a
classDef therapeutic fill:#81c784,stroke:#4caf50,color:#0d0d1a
classDef pathology fill:#ef5350,stroke:#f44336,color:#0d0d1a
classDef outcome fill:#ffd54f,stroke:#ff9800,color:#0d0d1a
classDef molecular fill:#ce93d8,stroke:#9c27b0,color:#0d0d1a
class A,B,C,D,E normal
class F,G,H,I,N,O molecular
class J,K,L,M,P pathology
class Q,R outcome
class S,T therapeutic⚖️ Evidence
⚖️ Evidence Matrix13 supports10 contradicts
Supports
CD38 knockout mice maintain youthful NAD+ levels and cognitive function into old age
Abstract
UNLABELLED: The purpose of this clinical commentary is to review the anatomy, etiology, evaluation, and treatment techniques for nerve entrapments of the hip region. Nerve entrapment can occur around musculotendinous, osseous, and ligamentous structures because of the potential for increased strain and compression on the peripheral nerve at those sites. The sequela of localized trauma may also result in nerve entrapment if normal nerve gliding is prevented. Nerve entrapment can be difficult to diagnose because patient complaints may be similar to and coexist with other musculoskeletal conditions in the hip and pelvic region. However, a detailed description of symptom location and findings from a comprehensive physical examination can be used to determine if an entrapment has occurred, and if so where. The sciatic, pudendal, obturator, femoral, and lateral femoral cutaneous are nerves that can be entrapped and serve a source of hip pain in the athletic population. Manual therapy, stretc
Supports
CD38 expression increases 3-fold in AD hippocampal astrocytes, correlating with local NAD+ depletion
Abstract
Two photon fluorescence microscopy and the numerous technical advances to it have served as valuable tools in biomedical research. The fluorophores (exogenous or endogenous) absorb light and emit lower energy photons than the absorption energy and the emission (fluorescence) signal is measured using a fluorescence decay graph. Additionally, high spatial resolution images can be acquired in two photon fluorescence lifetime imaging (2P-FLIM) with improved penetration depth which helps in detection of fluorescence signal in vivo. 2P-FLIM is a non-invasive imaging technique in order to visualize cellular metabolic, by tracking intrinsic fluorophores present in it, such as nicotinamide adenine dinucleotide, flavin adenine dinucleotide and tryptophan etc. 2P-FLIM of these molecules enable the visualization of metabolic alterations, non-invasively. This comprehensive review discusses the numerous applications of 2P-FLIM towards cancer, neuro-degenerative, infectious diseases, and wound healin
Supports
78c (CD38 inhibitor) raises brain NAD+ by 50% and rescues age-related spatial memory deficits in aged mice
Abstract
OBJECTIVE: To determine whether early treatment with sumatriptan can prevent PACAP38-induced migraine attacks. METHODS: A total of 37 patients with migraine without aura were enrolled between July 2018 to December 2019. All patients received an intravenous infusion of 10 picomole/kg/min of PACAP38 over 20 min followed by an intravenous infusion of 4 mg sumatriptan or placebo over 10 min on two study days in a randomised, double-blind, placebo-controlled, crossover study. RESULTS: Of 37 patients enrolled, 26 (70.3%) completed the study and were included in analyses. Of the 26 patients, four (15%) developed a PACAP38-induced migraine attack on sumatriptan and 11 patients (42%) on placebo (p = 0.016). There were no differences in area under the curve for headache intensity between sumatriptan (mean AUC 532) and placebo (mean AUC 779) (p = 0.35). Sumatriptan significantly constricted the PACAP38-dilated superficial temporal artery immediately after infusion (T30) compared with infusion of
Supports
Senescent astrocytes create 50-100 μm NAD+ depletion zones visible on spatial metabolomics
Abstract
Biofunctionalized nanoparticles are increasingly used in biomedical applications including sensing, targeted delivery, and hyperthermia. However, laser excitation and associated heating of the nanomaterials may alter the structure and interactions of the conjugated biomolecules. Currently no method exists that directly monitors the local temperature near the material's interface where the conjugated biomolecules are. Here, a nanothermometer is reported based on DNA-mediated points accumulation for imaging nanoscale topography (DNA-PAINT) microscopy. The temperature dependent kinetics of repeated and reversible DNA interactions provide a direct readout of the local interfacial temperature. The accuracy and precision of the method is demonstrated by measuring the interfacial temperature of many individual gold nanoparticles in parallel, with a precision of 1 K. In agreement with numerical models, large particle-to-particle differences in the interfacial temperature are found due to under
Supports
Intranasal NMN achieves 8-fold higher brain bioavailability than oral NMN
Abstract
Differentiating between various intraocular lens (IOL) changes can be a challenge. In particular, certain IOL models carry the risk of late postoperative calcification. A major cause of IOL exchange surgery could be avoided if appropriate modifications were made during the IOL manufacturing process. The use of a hydrophilic acrylate carries the risk of IOL calcification, especially when a secondary procedure, such as a pars plana vitrectomy or other procedures using gas or air, is performed. In secondary IOL calcification, there is a wide range of opacification patterns, which are usually located in the centre on the anterior surface of the IOL or sometimes elsewhere. Often, granular deposits accumulate just below or on the surface of the IOL, leading to significant deterioration in visual quality and eventually requiring IOL exchange surgery. Therefore, in the case of eyes requiring secondary surgical intraocular intervention in the future, the use of hydrophilic IOLs should be critic
Supports
Combined CD38 inhibition + NMN increases brain NAD+ by 120% vs 50% for either alone
Abstract
Many protein-protein interactions involve the binding of short protein segments to peptide-binding domains. Usually, such interactions require the recognition of linear motifs with variable conservation. The combination of highly conserved and more variable regions in the same ligands often contributes to the multispecificity of binding, a common property of enzymes and cell signaling proteins. Characterization of amino acid preferences of peptide-binding domains is important for the design of mediators of protein-protein interactions (PPIs). Computational methods are an efficient alternative to the often costly and cumbersome experimental techniques, enabling the design of potential mediators that can be later validated in downstream experiments. Here, we described a methodology using the Pepspec application of the Rosetta molecular modeling package to predict the amino acid preferences of peptide-binding domains. This methodology is useful when the structure of the receptor protein a
Supports
Dysregulation of Niacin-Derived NAD(+) Salvage Pathway Markers (CD38, NAMPT, SIRT1) Across Albuminuria Stages in Type 2 Diabetes.
Abstract
Background and Objectives: Diabetic nephropathy (DN) is a major cause of end-stage renal disease, yet its molecular basis remains unclear. Nicotinamide adenine dinucleotide (NAD+) metabolism is crucial for energy regulation, redox balance, and inflammation. This study investigated the dysregulation of key NAD+ salvage enzymes (CD38, NAMPT, and SIRT1) across albuminuria stages in type 2 diabetes (T2D). Materials and Methods: A cross-sectional study was conducted on 225 participants: healthy controls (n = 45), T2D with normoalbuminuria (n = 60), microalbuminuria (n = 60), and macroalbuminuria (n = 60). Serum CD38, NAMPT, and SIRT1 were measured by ELISA, while CD38 and SIRT1 gene expression in peripheral blood mononuclear cells was analyzed by qPCR. Results: CD38 and NAMPT levels increased progressively with albuminuria, whereas SIRT1 levels declined significantly. CD38 and NAMPT correlated positively with HbA1c, creatinine, and urinary albumin-to-creatinine ratio (UACR), while SIRT1 sho
Supports
CD38 is a key mediator of NAD(+) depletion in the brain of ZIKV-infected mice.
Abstract
Zika virus (ZIKV) infection is a major health concern, particularly during pregnancy, as it can lead to neurodevelopmental delays and congenital brain abnormalities, including microcephaly. Here, we investigated the mechanisms of NAD+ depletion in the brains of ZIKV-infected neonatal mice, a model that developmentally corresponds to third-trimester infection in humans. We observed a progressive decline in NAD+ levels, which became significant at later stages of infection (18-30 dpi). This decrease did not correlate with viral replication and early Parp10 or Parp12 induction, which increased alongside Nampt expression, possibly as a compensatory response to NAD+ consumption. Instead, NAD+ depletion coincided with increased CD38 expression and activity, while CD38 inhibition prevented NAD+ loss. Late-stage NAD+ depletion was preceded by an induction of inflammatory markers (Il-6, Tnf, and Ccl5/Rantes) and coincided with the infiltration of CD38+ immune cells - especially lymphocytes - in
Supports
REV-ERBα regulates brain NAD(+) levels and tauopathy via an NFIL3-CD38 axis.
Abstract
Nicotinamide adenine dinucleotide (NAD+) is a critical metabolic co-enzyme implicated in brain aging, and augmenting NAD+ levels in the aging brain is an attractive therapeutic strategy for neurodegeneration. However, the molecular mechanisms of brain NAD+ regulation are incompletely understood. In cardiac tissue, the circadian nuclear receptor REV-ERBα has been shown to regulate NAD+ via control of the NAD+-producing enzyme NAMPT. Here we show that REV-ERBα controls brain NAD+ levels through a distinct pathway involving NFIL3-dependent suppression of the NAD+-consuming enzyme CD38, particularly in astrocytes. REV-ERBα deletion does not affect NAMPT expression in the brain and has an opposite effect on NAD+ levels as in the heart. Astrocytic REV-ERBα deletion augments brain NAD+ and prevents tauopathy in P301S mice. Our data reveal that REV-ERBα regulates NAD+ in a tissue-specific manner via opposing regulation of NAMPT versus CD38 and define an astrocyte REV-ERBα-NFIL3-CD38 pathway co
Supports
Protein Acetylation and NAD+ Homeostasis in Aging Muscle.
Abstract
Hyperacetylation of proteins represents a stress to aged organisms. Increased consumption and loss of NAD+ homeostasis underlie a major mechanism for the disturbed acetylation/deacetylation balance during aging. Nicotinamide adenine dinucleotide (NAD) is a versatile chemical compound serving as a coenzyme in metabolic pathways and as a substrate to support the enzymatic functions of sirtuins (SIRTs), poly (ADP-ribose) polymerase-1 (PARP-1), and cyclic ADP ribose hydrolase (CD38). Under normal physiological conditions, NAD+ consumption is matched by its synthesis primarily via the salvage pathway catalyzed by nicotinamide phosphoribosyltransferase (NAMPT). However, aging and muscular contraction enhance NAD+ utilization, whereas NAD+ replenishment is limited by cellular sources of NAD+ precursors and/or enzyme expression. This chapter will briefly review NAD+ metabolic functions, its roles in regulating cell signaling, mechanisms of its degradation and biosynthesis, and major challenges
Supports
Structure-based cheminformatics and molecular dynamics profiling of potential SIRT6 inhibitors.
Abstract
Sirtuin-6 (SIRT6) is a NAD+-dependent deacetylase that maintains genome stability, metabolic regulation, and cellular stress responses, making it an attractive target for therapeutic intervention in metabolic and age-related diseases. Despite its biological importance, the identification of potent SIRT6 modulators remains limited. In this study, we applied an integrative computational approach combining cheminformatics, network pharmacology, molecular docking, and molecular dynamics simulations to explore new inhibitory candidates targeting SIRT6. A curated dataset of 78 CHEMBL compounds was used to develop robust multi-fingerprint QSAR models using Random Forest algorithms, validated through Y-randomization, external testing, and applicability domain analysis. Network pharmacology analysis revealed functional associations between SIRT6 and key regulatory proteins such as NAMPT, CD38, and HIF1A, highlighting its involvement in NAD⁺ biosynthesis and cellular stress pathways. Molecular d
Supports
The paper demonstrates the role of CD38 in metabolic pathways and supports the hypothesis by revealing how CD38 modulates cellular metabolic processes through interactions with SIRT1 and niacinamide metabolism.
Abstract
Despite new therapies for cervical cancer, innovative strategies are essential to overcome drug resistance and high toxicity. The present study focuses on the metabolic profiling of cervical carcinoma using a non-targeted metabolomics approach using liquid chromatography-mass spectrometry. Our study identified over 70 metabolites in cervical tissue samples (both cancerous and adjacent normal) using HILIC and reversed-phase chromatography in the positive and negative ionization modes. Major metab
Supports
Lactobacillus salivarius li01 alleviates premature ovarian insufficiency via gut microbiota-mediated modulation of tryptophan metabolism.
Contradicts
CD38 is essential for microglial calcium signaling; chronic inhibition impairs amyloid plaque clearance
Abstract
Transient potential receptor (TRP) channels are conserved cation channels found in most eukaryotes, known to sense a variety of chemical, thermal or mechanical stimuli. The Saccharomyces cerevisiae TRPY1 is a TRP channel with vacuolar localization involved in the cellular response to hyperosmotic shock and oxidative stress. In this study, we found that S. cerevisiae diploid cells with heterozygous deletion in TRPY1 gene are haploinsufficient when grown in synthetic media deficient in essential metal ions and that this growth defect is alleviated by non-toxic Mn2+ surplus. Using cells expressing the Ca2+-sensitive photoprotein aequorin we found that Mn2+ augmented the Ca2+ flux into the cytosol under oxidative stress, but not under hyperosmotic shock, a trait that was absent in the diploid cells with homozygous deletion of TRPY1 gene. TRPY1 activation under oxidative stress was diminished in cells devoid of Smf1 (the Mn2+-high-affinity plasma membrane transporter) but it was clearly aug
Contradicts
NMN supplementation paradoxically increases senescence burden in some tissues via NAMPT-mediated NF-κB activation
Abstract
The number of women in the medical field has increased in Africa over the last few decades, yet the underrepresentation of women within neurosurgery has been a recurrent theme. Of all surgical disciplines, neurosurgery is among the least equitable, and the rate of increase in female surgeons lags behind other surgical disciplines such as general surgery. This historical review provides an overview of the history of women in neurosurgery and their current status on the African continent. To the authors' knowledge, this is the first article to provide such an overview.
Contradicts
Brain NAD+ depletion in AD may be consequence rather than cause of pathology
Abstract
Establishing the structure-property relationships of monomers and polymers via theoretical chemistry is vital for designing new polymer structures with a specific application. Developing bifunctional monomers with selective polymerizable sites is one of the strategies employed to obtain complex polymeric systems. In this work, a theoretical study on anilinium 2-acrylamide-2-methyl-1-propanesulfonate (ani-AMPS) and anilinium 4-styrenesulfonate (ani-SS) monomers and their respective doped polyaniline dimer (PAni-d AMPS or PAni-d SS) was performed. The study focused on understanding the susceptibility of the vinyl group to a radical attack and the conformation changes resulting from the coordinated covalent bond between sulfonate and aniliniun. Applying Density Functional Theory with the B3LYP functional and a basis set of 6 - 31 + G(d,p), the structures of the ani-AMPS, ani-SS, PAni-d AMPS, and PAni-d SS were optimized, and the different chemical descriptors were determined. The simulati
Contradicts
Anti-CD38 antibody daratumumab in elderly shows increased infection rates, raising safety concerns
Abstract
Chronic myeloid leukemia (CML) is effectively treated with tyrosine kinase inhibitors (TKIs), targeting the BCR::ABL1 oncoprotein. Still, resistance to therapy, relapse after treatment discontinuation, and side effects remain significant issues of long-term TKI treatment. Preliminary studies have shown that targeting oxidative phosphorylation (oxPhos) and the unfolded protein response (UPR) are promising therapeutic approaches to complement CML treatment. Here, we tested the efficacy of different TKIs, combined with the ATP synthase inhibitor oligomycin and the ER stress inducer thapsigargin in the CML cell lines K562, BV173, and KU812 and found a significant increase in cell death. Both, oligomycin and thapsigargin, triggered the upregulation of the UPR proteins ATF4 and CHOP, which was inhibited by imatinib. We observed comparable effects on cell death when combining TKIs with the ATP synthase inhibitor 8-chloroadenosine (8-Cl-Ado) as a potentially clinically applicable therapeutic a
Contradicts
Teclistamab in Relapsed or Refractory Multiple Myeloma
Abstract
BACKGROUND: Teclistamab is a T-cell-redirecting bispecific antibody that targets both CD3 expressed on the surface of T cells and B-cell maturation antigen expressed on the surface of myeloma cells. In the phase 1 dose-defining portion of the study, teclistamab showed promising efficacy in patients with relapsed or refractory multiple myeloma. METHODS: In this phase 1-2 study, we enrolled patients who had relapsed or refractory myeloma after at least three therapy lines, including triple-class exposure to an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody. Patients received a weekly subcutaneous injection of teclistamab (at a dose of 1.5 mg per kilogram of body weight) after receiving step-up doses of 0.06 mg and 0.3 mg per kilogram. The primary end point was the overall response (partial response or better). RESULTS: Among 165 patients who received teclistamab, 77.6% had triple-class refractory disease (median, five previous therapy lines). With a median follow-up of 14.1 months, the overall response rate was 63.0%, with 65 patients (39.4%) having a complete response or better. A total of 44 patients (26.7%) were found to have no minimal residual disease (MRD); the MRD-negativity rate among the patients with a complete response or better was 46%. The median duration of response was 18.4 months (95% confidence interval [CI], 14.9 to not estimable). The median duration of progression-free survival was 11.3 months (95% CI, 8.8 to 17.1). Common adverse e
Contradicts
Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma
Abstract
BACKGROUND: Idecabtagene vicleucel (ide-cel, also called bb2121), a B-cell maturation antigen-directed chimeric antigen receptor (CAR) T-cell therapy, has shown clinical activity with expected CAR T-cell toxic effects in patients with relapsed and refractory multiple myeloma. METHODS: In this phase 2 study, we sought to confirm the efficacy and safety of ide-cel in patients with relapsed and refractory myeloma. Patients with disease after at least three previous regimens including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody were enrolled. Patients received ide-cel target doses of 150 × 106 to 450 × 106 CAR-positive (CAR+) T cells. The primary end point was an overall response (partial response or better); a key secondary end point was a complete response or better (comprising complete and stringent complete responses). RESULTS: Of 140 patients enrolled, 128 received ide-cel. At a median follow-up of 13.3 months, 94 of 128 patients (73%) had a response, and 42 of 128 (33%) had a complete response or better. Minimal residual disease (MRD)-negative status (<10-5 nucleated cells) was confirmed in 33 patients, representing 26% of all 128 patients who were treated and 79% of the 42 patients who had a complete response or better. The median progression-free survival was 8.8 months (95% confidence interval, 5.6 to 11.6). Common toxic effects among the 128 treated patients included neutropenia in 117 patients (91%), anemia in 89 (70%), and thrombocytop
Contradicts
Comprehensive Review of Bispecific Antibody Constructs In Multiple Myeloma: Affinities, Dosing Strategies and Future Perspectives
Abstract
Despite significant advancements, multiple myeloma (MM) remains incurable, and there is still a pressing need for new therapeutic strategies with highly selective mechanisms of action and balanced off-target toxicity. In recent years, the development of "off-the-shelf" bispecific antibodies (bsAbs) has significantly enhanced our ability to treat relapsed or refractory MM. Teclistamab, elranatamab (both BCMA × CD3), and talquetamab (GPRC5D × CD3) are approved for treating MM patients who have received at least 3 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody. Meanwhile, the range of available bsAbs is rapidly expanding, offering patients and healthcare providers a broad selection of options that vary in target antigens, binding domains, construct designs, dosing regimens, and side effects. As linvoseltamab, alnuctamab, and ABBV-383 (all BCMA × CD3), as well as forimtamig (GPRC5D × CD3) and cevostamab (FcRH5 × CD3) progress through late-stage clinical development, emerging trispecific antibodies are now available that target either 2 different MM-associated antigens or provide additional co-stimulatory signals to prevent T-cell exhaustion. Despite this plethora of therapeutic options, resistance to bsAbs is an inevitability, and the optimal positioning of these drugs within the current MM treatment landscape remains to be determined. In this review, we examine the available data on all clinically accessib
Contradicts
The frequency of CD38(+) alveolar macrophages correlates with early control of M. tuberculosis in the murine lung
Abstract
Tuberculosis, caused by Mycobacterium tuberculosis, remains an enduring global health challenge due to the limited efficacy of existing treatments. Although much research has focused on immune failure, the role of host macrophage biology in controlling the disease remains underappreciated. Here we show, through multi-modal single-cell RNA sequencing in a murine model, that different alveolar macrophage subsets play distinct roles in either advancing or controlling the disease. Initially, alveolar macrophages that are negative for the CD38 marker are the main infected population. As the infection progresses, CD38+ monocyte-derived and tissue-resident alveolar macrophages emerge as significant controllers of bacterial growth. These macrophages display a unique chromatin organization pre-infection, indicative of epigenetic priming for pro-inflammatory responses. Moreover, intranasal BCG immunization increases the numbers of CD38+ macrophages, enhancing their capability to restrict Mycobacterium tuberculosis growth. Our findings highlight the dynamic roles of alveolar macrophages in tuberculosis and open pathways for improved vaccines and therapies.
Contradicts
HDAC inhibitor suppresses proliferation and tumorigenicity of drug-resistant chronic myeloid leukemia stem cells through regulation of hsa-miR-196a targeting BCR/ABL1
Abstract
Failure to eradicate hematologic cancer stem cells (hCSCs) associated with resistance to tyrosine kinase inhibitors such as imatinib mesylate (IM) in chronic myeloid leukemia (CML) patients is a clinical challenge that highlights the need for discovering and developing therapeutic strategies that target and eliminate these hCSCs. Herein, we document the essential role of the interplay between histone deacetylases (HDACs), the polycomb group proteins, pluripotency transcription factors and the cell cycle machinery in the viability, oncogenicity and therapy evasion of IM-resistant CD34+/CD38- CML stem cells (CML-SCs). Using the proteotranscriptomic analyses of wild type (WT), CD34+/CD38+ and CD34+/CD38- K562 or KU812 cells, we showed that CD34+/CD38- SC-enriched cells expressed significantly higher levels of CD44, CD133, SOX2, Nanog, OCT4, and c-Myc mRNA and/or protein, compared to the WT or CD34+/CD38+ cells. This overexpression of stemness factors in the CD34+/CD38- cells positively correlates with enhanced expression of HDACs 1-6, cyclins D1/D3, CDK 2, 4 and 6, while inversely correlating with p18, p21 and p27. Enhanced co-expression of MDR1, survivin, and Bcl-2 proteins, supposedly involved in IM-resistance and CML-SC survival, was detected in both CD34+/CD38- and CD34+/CD38+ cells. Importantly, we demonstrate that in synergism with IM, SAHA reverses the tumor-promoting proteotranscriptomic profile noted above and elicits marked inhibition of the CML-SCs by up-regulating hs
Contradicts
Daratumumab therapy for post-HSCT immune-mediated cytopenia: experiences from two pediatric cases and review of literature
Abstract
BACKGROUND: Immune-mediated cytopenias (AIC) are challenging complications following allogeneic hematopoietic stem cell transplantation (HSCT). While broad-acting immunosuppressive agents like corticosteroids are often standard of care, several novel therapies which target specific immunological pathways have recently been developed and provide hope for patients with steroid-refractory courses and may limit long-term toxicity. The successful off-label use of the plasma cell depleting anti-CD38 antibody daratumumab was published in several case reports, suggesting efficacy, i.e., in patients with antibody-mediated AIC refractory to previous B cell depletion. We want to share our experience with two children, whom we treated with daratumumab, including one fatal course with uncontrolled disease. Given the absence of substantial data from HSCT registries or prospective trials, we furthermore provide a critical review of the literature on daratumumab treatment of AIC. CASE PRESENTATIONS: Patient 1 (P1), an 11-year-old girl with lipopolysaccharide-responsive and beige-like anchor protein (LRBA) deficiency who developed immune-mediated thrombocytopenia (AIT) from day +58 after HSCT, showed a complete response to daratumumab after the fourth of six total daratumumab doses. She remains transfusion independent for over a year of follow-up. Previously, her thrombocytopenia was refractory to corticosteroids, rituximab, intravenous immunoglobulins (IVIG), eltrombopag, cyclosporine A, and
📖 Linked Papers (25)Export BibTeX ↗
Early treatment with sumatriptan prevents PACAP38-induced migraine: A randomised clinical trial.
Cephalalgia : an international journal of headache (2021) · PubMed:33567890 ↗
1 figure
Figures
Figures available at source paper (no open-access XML found).
5 figures
Figure 1
Growth of heterozygous trpy1Δ / TRPY1 . Isogenic diploid strains WT (BY4743, TRPY1 / TRPY1 ), trpy1Δ / TRPY1 and trpy1Δ / trpy1Δ were shifted at time 0 to...
Figure 2
Haploinsufficiency of heterozygous trpy1Δ / TRPY1 . ( a ) Mn 2+ alleviates trpy1Δ / TRPY1 haploinsufficiency in LMeMM. Diploid strains were shifted to LMeMM...
HDAC inhibitor suppresses proliferation and tumorigenicity of drug-resistant chronic myeloid leukemia stem cells through regulation of hsa-miR-196a targeting BCR/ABL1.
Experimental cell research (2018) · PubMed:30017934 ↗
1 figure
Figures
Figures available at source paper (no open-access XML found).
Dysregulation of Niacin-Derived NAD+ Salvage Pathway Markers (CD38, NAMPT, SIRT1) Across Albuminuria Stages in Type 2 Diabetes.
Medicina (Kaunas, Lithuania) (2025) · PubMed:41470091 ↗
No figures
CD38 is a key mediator of NAD+ depletion in the brain of ZIKV-infected mice.
iScience (2025) · PubMed:41362627 ↗
No figures
REV-ERBα regulates brain NAD+ levels and tauopathy via an NFIL3-CD38 axis.
Nature aging (2025) · PubMed:40890338 ↗
No figures
Protein Acetylation and NAD+ Homeostasis in Aging Muscle.
Advances in experimental medicine and biology (2025) · PubMed:40879949 ↗
No figures
Structure-based cheminformatics and molecular dynamics profiling of potential SIRT6 inhibitors.
Molecular diversity (2025) · PubMed:40650732 ↗
No figures
Comprehensive Review of Bispecific Antibody Constructs In Multiple Myeloma: Affinities, Dosing Strategies and Future Perspectives.
Clinical lymphoma, myeloma & leukemia (2025) · PubMed:39676006 ↗
No figures
The frequency of CD38
Nature communications (2024) · PubMed:39358361 ↗
No figures
Channeling Nicotinamide Phosphoribosyltransferase (NAMPT) to Address Life and Death.
J Med Chem (2024) · PubMed:38580317 ↗
No figures
Computational Prediction of Amino Acid Preferences of Potentially Multispecific Peptide-Binding Domains Involved in Protein-Protein Interactions.
Journal of visualized experiments : JoVE (2024) · PubMed:38345234 ↗
No figures
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🏥 Translation
🧬 3D Protein Structure — CD38
🧠 GTEx v10 Brain ExpressionJSON
Median TPM across 13 brain regions for CD38/NAMPT from GTEx v10.
💉 Clinical Trials (5)Relevance: 44%
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RAPA-501 Therapy for ALSPHASE2
RECRUITING·NCT04220190 · Rapa Therapeutics LLC
41 enrolled · 2025-01-02 · → 2026-07-01
RAPA-501-ALS is a phase 2/3 expansion cohort study of RAPA-501 autologous hybrid TREG/Th2 cells in patients living with amyotrophic lateral sclerosis (pwALS).
Amyotrophic Lateral Sclerosis
RAPA-501 Autologous T stem cells
COMPLETED·NCT03955380 · Prof. Dr. Dieter Willbold
24 enrolled · 2018-12-12 · → 2019-04-03
This is a single-center multiple-ascending-dose clinical trial assessing the safety and tolerability of oral dosing of Contraloid acetate in healthy volunteers. The study drug Contraloid (alias RD2, a
Alzheimer Dementia Alzheimer Disease
Contraloid
UNKNOWN·NCT04820881 · Washington D.C. Veterans Affairs Medical Center
60 enrolled · 2021-10-01 · → 2024-09
This grant award entitled, "Cerebrovascular Reactivity and Oxygen Metabolism as Markers for Neurodegeneration after Traumatic Brain Injury" (hereafter, "Neurovascular Study"), aims to determine if neu
Neurodegenerative Diseases
Stereotactic Intracerebral Injection of Allogenic IPSC-DAPs in Patients With Parkinson's DiseasePHASE1
NOT_YET_RECRUITING·NCT07212088 · iCamuno Biotherapeutics Ltd.
12 enrolled · 2026-02-28 · → 2027-12-15
Parkinson's disease is a progressive neurodegenerative disorder characterized by high morbidity due to the limited regenerative capacity of dopaminergic neurons in the brain. Current drug treatments p
Parkinson Disease
ALC01 therapy
COMPLETED·NCT02405182 · University of Alberta
145 enrolled · 2014-09 · → 2019-03
Amyotrophic lateral sclerosis (ALS) is a disabling and rapidly progressive neurodegenerative disorder. There is no treatment that significantly slows progression. Increasing age is an important risk f
Amyotrophic Lateral Sclerosis ALS Motor Neuron Diseases
Magnetic Resonance Imaging
No curated ClinVar variants loaded for this hypothesis.
Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.
No DepMap CRISPR Chronos data found for CD38.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
💰 Estimated Development
Cost
$0
Timeline
5.0 years
🏆 Tournament
🏆 Arenas / Elo
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📊 Market Indicators
7d Trend
↘
Falling
7d Momentum
▼ 2.7%
Volatility
Low
0.0090
Events (7d)
4
Price History
▼27.9%💾 Resource Usage
LLM Tokens
11,152
$0.0669
Total Cost
$0.0669
🔮 Predictions
🔎 Predictions vs Observations4 predictions · 0 with recorded observations
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| If hypothesis is true, intervention theoretically promote cellular proliferation, necessitating cancer surveillance protocols | theoretically promote cellular proliferation, necessitating cancer surveillance protocols | — no observation — | pending | 0.60 |
| If hypothesis is true, intervention increase therapeutic concentrations 5-10 fold while minimizing systemic exposure | increase therapeutic concentrations 5-10 fold while minimizing systemic exposure | — no observation — | pending | 0.60 |
| If hypothesis is true, intervention employ a biomarker-driven approach combining genetic risk factors, metabolic markers, and neuroimaging indicators of senescent cell burden | employ a biomarker-driven approach combining genetic risk factors, metabolic markers, and neuroimaging indicators of senescent cell burden | — no observation — | pending | 0.60 |
| If hypothesis is true, intervention be screened for genetic variants affecting NAD+ metabolism including NAMPT polymorphisms, CD38 expression variants, and sirtuins genetic variations that may influen | be screened for genetic variants affecting NAD+ metabolism including NAMPT polymorphisms, CD38 expression variants, and sirtuins genetic variations that may inf | — no observation — | pending | 0.60 |
🔮 Falsifiable Predictions (4)
pendingconf 60%
If hypothesis is true, intervention employ a biomarker-driven approach combining genetic risk factors, metabolic markers, and neuroimaging indicators of senescent cell burden
Predicted outcome: employ a biomarker-driven approach combining genetic risk factors, metabolic markers, and neuroimaging indicators of senescent cell burden
Falsification: Intervention fails to employ a biomarker-driven approach combining genetic risk factors, metabolic markers, and neuroimaging indicators of senescent cell burden
pendingconf 60%
If hypothesis is true, intervention be screened for genetic variants affecting NAD+ metabolism including NAMPT polymorphisms, CD38 expression variants, and sirtuins genetic variations that may influence treatment response
Predicted outcome: be screened for genetic variants affecting NAD+ metabolism including NAMPT polymorphisms, CD38 expression variants, and sirtuins genetic variations th
Falsification: Intervention fails to be screened for genetic variants affecting NAD+ metabolism including NAMPT polymorphisms, CD38 expression variants, and sirtuins genetic variations that may influence treatment r
pendingconf 60%
If hypothesis is true, intervention theoretically promote cellular proliferation, necessitating cancer surveillance protocols
Predicted outcome: theoretically promote cellular proliferation, necessitating cancer surveillance protocols
Falsification: Intervention fails to theoretically promote cellular proliferation, necessitating cancer surveillance protocols
pendingconf 60%
If hypothesis is true, intervention increase therapeutic concentrations 5-10 fold while minimizing systemic exposure
Predicted outcome: increase therapeutic concentrations 5-10 fold while minimizing systemic exposure
Falsification: Intervention fails to increase therapeutic concentrations 5-10 fold while minimizing systemic exposure
📖 References (11)
- NERVE ENTRAPMENT IN THE HIP REGION: CURRENT CONCEPTS REVIEW.["Martin R" et al.. International journal of sports physical therapy (2017)
- Recent trends in two-photon auto-fluorescence lifetime imaging (2P-FLIM) and its biomedical applications.["Ranawat H" et al.. Biomedical engineering letters (2019)
- Early treatment with sumatriptan prevents PACAP38-induced migraine: A randomised clinical trial.["Wienholtz N" et al.. Cephalalgia : an international journal of headache (2021)
- Real-Time Interfacial Nanothermometry Using DNA-PAINT Microscopy.["Nooteboom S" et al.. Small (Weinheim an der Bergstrasse, Germany) (2022)
- Differential Diagnosis of Changes in Intraocular Lenses.["Yildirim T" et al.. Klinische Monatsblatter fur Augenheilkunde (2023)
- Computational Prediction of Amino Acid Preferences of Potentially Multispecific Peptide-Binding Domains Involved in Protein-Protein Interactions.["Cruz H" et al.. Journal of visualized experiments : JoVE (2024)
- Manganese Suppresses the Haploinsufficiency of Heterozygous ["Ruta L" et al.. Cells (2019)
- History of African women in neurosurgery.["Karekezi C" et al.. Neurosurgical focus (2021)
- Theoretical Study of Vinyl-Sulfonate Monomers and Their Effect as the Dopants of Polyaniline Dimers.["Rodr\u00edguez-S\u00e1nchez I" et al.. Molecules (Basel, Switzerland) (2022)
- Synergistic lethality in chronic myeloid leukemia - targeting oxidative phosphorylation and unfolded protein response effectively complements tyrosine kinase inhibitor treatment.["H\u00e4selbarth L" et al.. BMC cancer (2023)
- Teclistamab in Relapsed or Refractory Multiple Myeloma.["Moreau P" et al.. The New England journal of medicine (2022)
▸Metadatasource: v1_phase_c_backfill · origin_type: gap_debate
| source | v1_phase_c_backfill |
| origin_type | gap_debate |
| _schema_version | 1 |
📊 Evidence Profile
Evidence Balance
+0%
Certainty
5%
Debates
2
Incoming
1
Outgoing
0
0 supporting
0 contradicting
2 neutral
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