DeCure's autonomous Immuno AI scientist is researching a drug-repurposing hypothesis for graft versus host disease — screening already-approved drugs against its 50-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleGraft versus host disease maps to a 50-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
approvedRuxolitinibApproved drug
Structures already discussed alongside graft versus host disease in the retrieved literature, rendered from public PubChem SMILES. Which drugs appear here reflects the evidence found, not a ranked prediction.
Molecular view
Human JAK2 JH1 domain — Ruxolitinib has a real, experimentally solved structure in complex with this target (PDB 6WTN, 1.83 Å). This is the drug's own deposited structure, not a prediction, and confirms it is a structurally characterised molecule rather than an untested guess.
Loading structure…
helix sheet rxtdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 6WTN · 1.83 Å · ligand Ruxolitinib (RXT). Experimental structure, not a prediction.
What the evidence adds up to
In a cohort of 242 patients who survived more than 100 days after allogeneic peripheral blood stem cell transplantation, 181 (75%) had some manifestation of graft-versus-host disease after day 100. At onset, 13 (7%) had late acute graft-versus-host disease, 62 (34%) had classic chronic graft-versus-host disease, and 106 (59%) had the overlap subtype. Global severity of chronic graft-versus-host disease was mild in 25% of cases, moderate in 46%, and severe in 29%. Moderate or severe chronic graft-versus-host disease was independently associated with worse overall survival (hazard ratio 2.9, 95% CI 1.8–4.7, P < 0.0001) and worse non-relapse mortality (moderate versus mild: HR 3.86, P = 0.03; severe versus mild: HR 10.06, P < 0.001). Progressive onset and low platelet count at diagnosis were also significantly associated with overall survival. The occurrence and severity of chronic graft-versus-host disease was significantly associated with primary disease relapse.
A systematic review of enteral versus parenteral nutrition in adult patients undergoing haematopoietic stem cell transplantation identified four articles that met inclusion criteria. Three were observational studies; one was a randomised trial that ended prematurely. The limited evidence suggested that enteral nutrition may have a protective mechanism against advanced stages of graft-versus-host disease and may contribute to a decreased risk of infection-related death. No definitive conclusions could be drawn from the available data.
In a laboratory study using peripheral blood mononuclear cells from 20 participants, osteopontin enhanced the proliferative response of alloactivated cells in a mixed lymphocyte reaction. Statistically significant increases in proliferation were observed at osteopontin concentrations of 100, 200, 300 and 400 ng/mL (P = 0.013, P = 0.009, P = 0.003, P < 0.001, respectively). The stimulation index increased in a dose-dependent manner. Osteopontin did not affect cell viability. The authors concluded that osteopontin may affect outcomes after haematopoietic stem cell transplantation but that future investigation is needed to verify whether it could serve as a predictive or prognostic marker of graft-versus-host disease.
What is still missing is a prospective trial comparing enteral and parenteral nutrition with adequate power to detect differences in graft-versus-host disease severity or mortality, and clinical studies that measure osteopontin levels in patients and test whether they correlate with transplant outcomes in a way that could guide patient stratification or treatment decisions.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Haematologica · 2011 · 78 citations · open access
The global severity of chronic graft-versus-host disease, determined by National Institutes of Health consensus criteria, is associated with overall survival and non-relapse mortality
AbstractBACKGROUND: The 2005 National Institutes of Health Consensus Development Conference on chronic graft-versus-host disease proposed major changes in the classification and grading of severity of chronic graft-versus-host disease. DESIGN AND METHODS: We aimed to study the association of the proposed chronic graft-versus-host disease classification and global severity with transplantation outcomes among a consecutive series of patients who received pharmacokinetically-targeted doses of intravenous busulfan and fludarabine conditioning followed by transplantation of allogeneic peripheral blood stem cells. RESULTS: From a total cohort (n = 242) of patients surviving more than 100 days after hematopoietic stem cell transplantation, 181 (75% of those at risk) had some manifestations of graft-versus-host disease after day 100. Of these, at onset 13 (7%) had late acute graft-versus-host disease, 62 (34%) had classic chronic graft-versus-host disease, and 106 (59%) had the overlap subtype of chronic graft-versus-host disease. The global severity of the chronic graft-versus-host disease was mild in 25% of cases, moderate in 46%, and severe in 29%. Multivariable modeling demonstrated the independent association of global severity of chronic graft-versus-host disease with overall survival (moderate/severe versus mild; HR 2.9, 95% CI 1.8-4.7, P < 0.0001) and non-relapse mortality (moderate versus mild; HR 3.86, 95% CI 1.17-12.73, P = 0.03, and severe versus mild (HR 10.06, 95% CI 3.07-32.97, P < 0.001). The type of onset of progressive chronic graft-versus-host disease and the platelet count at the time of diagnosis of the disease were significantly associated with overall survival. The occurrence and severity of chronic graft-versus-host disease was also significantly associated with primary disease relapse. CONCLUSIONS: Patients with moderate to severe chronic graft-versus-host disease, as determined by National Institutes of Health Consensus criteria, have an inferior overall survival and worse non-relapse mortality. Clinical and research advances are needed to improve the outcomes of affected patients.
AbstractPURPOSE OF REVIEW: Chronic graft-versus-host disease is an important cause of late morbidity and mortality after allogeneic stem cell transplantation. With the renewed interest in its pathophysiology and treatment, this review discusses recent clinical and laboratory advances in this disease. Advances in pathophysiology, the relationship between chronic graft-versus-host disease and relapse incidence, and recent developments in the prophylaxis, initial therapy, and therapy for refractory disease are discussed. RECENT FINDINGS: A better understanding of the pathophysiology of chronic graft-versus-host disease, including the potential role of a coordinated B-cell and T-cell response, is demonstrated. Corticosteroids and cyclosporine or tacrolimus remain the standard as initial therapy. This combination is effective in the majority of affected patients, although therapy is often required for longer than 1 year. Although no strategy has been demonstrated to be effective in specifically preventing chronic graft-versus-host disease, several drugs have recently been demonstrated to be effective therapeutic agents for steroid-refractory disease. Agents such as mycophenolate mofetil, sirolimus, and rituximab have demonstrated response rates of greater than 60% in patients with steroid-refractory disease. SUMMARY: Renewed interest and understanding of chronic graft-versus-host disease have led to novel treatment strategies for steroid-refractory disease. A focus on the initial therapy and prophylaxis against chronic graft-versus-host disease is now warranted.
Update on the management of acute graft-versus-host disease
AbstractPURPOSE OF REVIEW: Acute graft-versus-host disease is one of the commonest complications after allogeneic stem cell transplantation. Recent advances in its prevention and therapy are giving new hope to patients with this disease. This review covers the major advances in prophylaxis and therapy for this problem. RECENT FINDINGS: The use of novel approaches for prophylaxis such as posttransplant cyclophosphamide and non-methotrexate-containing regimens is discussed. The results of therapy with new agents such as pentostatin, pulse cyclophosphamide, long-wavelength ultraviolet A phototherapy, and monoclonal antibodies such as denileukin diftitox or etanercept are reviewed. SUMMARY: Without question, outcome in patients who develop graft-versus-host disease is improving. With better supportive care, and more effective prophylaxis and therapy, these patients have an improved chance for full recovery. Patients should be enrolled, when possible, in studies aimed to prevent and treat graft-versus-host disease.
Clinical journal of oncology nursing · 2019 · 5 citations
Enteral Versus Parenteral Nutrition: Use in Adult Patients Undergoing Hematopoietic Stem Cell Transplantation
AbstractBACKGROUND: Pretransplantation chemotherapy and side effects of transplantation can cause reduced oral intake, contributing to malnutrition. OBJECTIVES: The aim was to evaluate the current evidence comparing enteral nutrition (EN) to parenteral nutrition in the adult hematopoietic stem cell transplantation (HSCT) population. METHODS: A systematic review was conducted in PubMed/MEDLINE®, CINAHL® Plus With Full Text (EBSCO), and Cochrane Library and produced 238 articles. Four articles met inclusion criteria. FINDINGS: Three studies were observational; one was a randomized trial that ended prematurely. Outcomes included tolerance of EN, incidences of graft-versus-host disease (GVHD), rate of infection, and mortality. This limited information suggests that EN may have a protective mechanism against advanced stages of GVHD and contribute to decreased risk of infection-related death.
Journal of Pre-Clinical and Clinical Research · 2019 · 2 citations · open access
Osteopontin enhances donor-specific alloreactivity of human peripheral blood mononuclear cells
AbstractIntroduction. Graft-versus-host disease (GVHD) is a serious complication after allogeneic haematopoietic stem cell transplantation (HSCT). Osteopontin (OPN) is a pleiotropic glycoprotein, which plays a significant role in the regulation of biomineralization, wound healing, and cellular immunity. Numerous studies have demonstrated that elevated OPN levels are associated with the pathogenesis of multiple autoimmune and inflammatory conditions. However, its role in GVHD and transplant immunology is poorly understood. Objective. The the aim of the study was to investigate the effects of OPN on human peripheral blood mononuclear cells (PBMCs) proliferation in a mixed lymphocyte reaction (MLR). Materials and method. PBMCs were isolated from the venous blood of 20 participants. Cell proliferation was examined at the DNA synthesis level by measurements of 3H-thymidine incorporation. Radioactivity was used to calculate the MLR stimulation index (SI). Cell viability was determined using the trypan blue exclusion method. Results. OPN enhanced the proliferative response of human alloactivated PBMCs in MLR. Statistically significant results were observed for OPN of 100, 200, 300 and 400 ng/mL (P = 0.013, P = 0.009; P = 0.003 and P < 0.001, respectively). Moreover, OPN increased SI in a dose-dependent way (P = 0.011, P = 0.007; P = 0.002 and P < 0.001, respectively). In addition, this protein did not affect cells viability. Conclusions. The results confirm the assumption that OPN may affect the outcome after HSCT; however, future investigation is needed to verify whether it may serve as a valuable predictive and prognostic marker of GVHD.
Efficacy and Safety of Ruxolitinib in Treatment of Steroid Refractory/Refractory Acute Graft-Versus-Host Disease: A Prospective Multicenter Research
AbstractAbstract Objectives To explore the efficacy and safety of ruxolitinib in the treatment of steroid refractory/refractory acute graft versus host disease (aGVHD). Methods A prospective analysis was conducted in the 31 steroid refractory/refractory aGVHD cases who treated with ruxolitinib from October 2017 to June 2018. The first dose of ruxolitinib was 5-10mg bid, and the dose was adjusted to 5mg qd for maintenance treatment when complete remission (CR) status lasted for 2 weeks after steroid refractory/refractory aGVHD turned into CR. Results Of all the 29 steroid refractory/refractory aGVHD patients, 15 patients were treated with ruxolitinib in case of disease progression after receiving at least one second-line treatment, and 14 cases directly with ruxolitinib after the occurrence of corticosteroid refractoriness. The time of starting ruxolitinib treatment after the occurrence of aGVHD was 10 (4-81) d, the median time of onset was 8 (3-18) d. The overall response rate was 89.6% (26/29) including 22 complete responses (75.9%), and 4 partial responses (13.8%). 12 patients with thrombocytopenia need to reduce the dose of ruxolitinib, and 1 patient withdrew treatment for obvious bleeding tendency. With the median follow-up 3 (2-8) months after treatment with ruxolitinib, 28 patients survived and 1 died of severe pneumonia related to aGVHD, and the overall survival was 96.6% (28/29). Conclusion Ruxolitinib is safe and effective in the treatment of steroid refractory/refractory aGVHD, and can be used as a second-line treatment for refractory aGVHD. Disclosures No relevant conflicts of interest to declare.
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
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