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bioRxiv2024

Aramchol attenuates fibrosis in mouse models of biliary fibrosis and blocks the TGFβ-induced fibroinflammatory mediators in cholangiocytes

BackgroundFibroinflammatory cholangiopathies, such as primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC), are characterized by inflammation and biliary fibrosis, driving disease-related complications. In biliary fibrosis, cholangiocytes activated by transforming growth factor-{beta} (TGF{beta}) release signals that recruit immune cells to drive inflammation and activate hepatic myofibroblasts to deposit the extracellular matrix (ECM). TGF{beta} regulates stearoyl-CoA desaturase (SCD), an enzyme that catalyzes the synthesis of monounsaturated fatty acids, in stimulating fibroinflammatory lipid signaling. However, the role of SCD or its inhibitor, Aramchol, has not been investigated in biliary fibrosis or TGF{beta}-mediated cholangiocyte activation. Method10-16-week-old multi-drug resistance 2 knockout (Mdr2-/-) and 3,5-diethoxycarboncyl-1,4-dihydrocollidine (DDC) diet-fed mice were orally gavaged daily with Aramchol at 12.5 mg/kg/day for 4 and 3 weeks, respectively. Liver and serum were harvested for the assessment of fibrosis and inflammation. Transformed human cholangiocyte cells (H69) and mouse large biliary epithelial cells (MLEs) were used to test the effects of the SCD inhibitor, Aramchol, at varying doses on TGF{beta}-mediated expression of fibroinflammatory signals and were confirmed in PSC-derived cholangiocytes (PSC-Cs) using ELISA, qPCR, and Western blot analyses. ResultsAramchol treatment of Mdr2-/- mice with established biliary fibrosis (treatment) and DDC diet-induced (prevention) models of cholestatic injury and fibrosis demonstrated significant reductions in both measures of ECM synthesis (mRNA expression of ECM components in the liver), collagen content of the liver (picrosirius red staining and hydroxyproline content) and myofibroblast activation (SMA staining). Il6 and Tnfa were also reduced with Aramchol in the liver. RNA-seq analysis of H69 cells showed that Aramchol co-treatment led to significant inhibition of TGF{beta}-induced hepatic fibrosis pathways while upregulating peroxisome proliferator-activated receptor (PPAR) signaling. SCD expression was significantly increased in TGF{beta}-treated H69 cells (2-fold, p<0.05). Aramchol in a dose-dependent manner significantly attenuated the increased expression of the fibrotic marker, plasminogen activator inhibitor-1 (PAI-1/SERPINE1), and hepatic stellate cell-activating genes (VEGFA and PDGFB) in TGF{beta}-activated H69 and MLEs. Aramchol also markedly reduced the expression of the inflammatory cytokine, interleukin 6 (IL6). SCD siRNA knockdown produced similar results in H69 cells. Furthermore, in PSC-Cs, the expressions of SCD, VEGFA and IL6 were significantly reduced with Aramchol. The expression of the anti-fibroinflammatory factors PPAR and -{gamma} were modestly increased in cholangiocyte cell lines with increased expression of PPAR-responsive genes and increased nuclear binding of DNA PPAR response elements with Aramchol co-treatment compared to TGF{beta} only. ConclusionAramchol, an SCD inhibitor, both attenuates and prevents biliary fibrosis in mouse models of cholestatic injury and fibrosis. This effect is partially due to Aramchol inhibiting TGF{beta}-induced fibroinflammatory mediators in cholangiocytes by upregulating PPAR and -{gamma} expression and activity. These findings, along with Aramchols excellent safety profile in clinical trials, provide the rationale for assessing Aramchol in further clinical studies in patients with biliary fibrosis, particularly PSC, where a treatment is desperately needed.

cell biology↗

bioRxiv2019

Combining Hypoxia-Activated Prodrugs and Radiotherapy in silico: Impact of Treatment Scheduling and the Intra-Tumoural Oxygen Landscape

Hypoxia-activated prodrugs (HAPs) present a conceptually elegant approach to not only overcome, but better yet, exploit intra-tumoural hypoxia. Despite being successful in vitro and in vivo, HAPs are yet to achieve successful results in clinical settings. It has been hypothesised that this lack of clinical success can, in part, be explained by the insufficiently stringent clinical screening selection of determining which tumours are suitable for HAP treatments. Taking a mathematical modelling approach, we investigate how tumour properties and HAP-radiation scheduling influence treatment outcomes in simulated tumours. The following key results are demonstrated in silico: (i) HAP and ionising radiation (IR) monotherapies may attack tumours in dissimilar, and complementary, ways. (ii) HAP-IR scheduling may impact treatment efficacy. (iii) HAPs may function as IR treatment intensifiers. (iv) The spatio-temporal intra-tumoural oxygen landscape may impact HAP efficacy. Our in silico framework is based on an on-lattice, hybrid, multiscale cellular automaton spanning three spatial dimensions. The mathematical model for tumour spheroid growth is parameterised by multicellular tumour spheroid (MCTS) data. Author SummaryWhen cancer patients present with solid tumours, the tumours often contain regions that are oxygen-deprived or, in other words, hypoxic. Hypoxic cancer cells are more resistant to conventional anti-cancer therapies, such as chemotherapy and radiotherapy, and therefore tumour hypoxia may complicate treatments. Hypoxia-activated prodrugs constitute a conceptually elegant approach to not only overcome, but better yet, exploit tumour hypoxia. Hypoxia-activated prodrugs are drugs that act as Trojan horses, they are theoretically harmless vehicles that are converted into warheads when they reach their targets: hypoxic tumour cells. Despite being conceptually clever and successful in experimental settings, hypoxia-activated prodrugs are yet to achieve successful results in clinical trials. It has been hypothesised that this lack of clinical success can, in part, be explained by an insufficiently stringent clinical screening selection of determining which tumours are suitable for hypoxia-activated prodrug treatments. In this article, we investigate how simulated tumours with different oxygen landscapes respond to anti-cancer treatments that include hypoxia-activated prodrugs, either alone or in combination with radiotherapy. Our simulation framework is based on a mathematical model that describes how individual cancer cells in a tumour divide and respond to treatments. We demonstrate that the efficacy of hypoxia-activated prodrugs depends on both the treatment scheduling, and on the oxygen landscape of the specific, simulated tumour.

cancer biology↗

bioRxiv2025

Cortical spectral rebalancing underlies pregabalin's efficacy in restless legs syndrome

Restless legs syndrome afflicts nearly half of all patients with end-stage renal disease, imposing profound burdens through relentless insomnia and functional decline. Dopaminergic agents--the established first-line therapy--trigger augmentation, a paradoxical intensification of symptoms that leaves patients worse than when they began treatment. The resultant therapeutic impasse has left a vulnerable population without effective recourse. Here we demonstrate that pregabalin, an 2{delta} calcium channel ligand with established renal safety, provides robust and sustained symptom relief in a randomized, placebo-controlled trial of dialysis patients with uremic restless legs syndrome. Clinical benefits emerged rapidly and intensified over three months, with pregabalin-treated patients showing more than twofold greater likelihood of categorical improvement in disease severity. In complementary animal electrophysiology experiments, pregabalin distinctively suppressed cortical hyperarousal--a hallmark of restless legs syndrome--by rebalancing low- and high-frequency oscillatory activity patterns, particularly in motor regions. This neural signature closely resembled that of gabapentin, another therapeutically effective 2{delta} ligand, suggesting convergent mechanisms. Beyond establishing pregabalin as an urgently needed alternative to dopaminergic therapy, our results demonstrate that cortical oscillatory profiling can reveal mechanistic convergence among candidate therapeutics, offering a rational preclinical screening strategy for neurological disorders before exposure of high-risk patient populations to experimental interventions. This framework may accelerate therapeutic discovery while reducing clinical trial risks in vulnerable populations.

neuroscience↗

bioRxiv2026

FLT-PET as predictive non-invasive biomarker for neoadjuvant therapy with Wee1 and ATR inhibitors

Besides immunotherapy, inhibitors of the DNA damage response (DDR) are currently one of the most promising contributors to improved cancer therapy. They exploit elevated replicative stress in cancer cells and often rely on synthetic lethality with existing gene deficiencies or between targeted pathways. In view of the absence of reliable histological biomarkers for replicative stress, this study examined [18F]-fluorothymidine (FLT) positron emission tomography (PET) as alternative or complementary approach to predict treatment response to DDR inhibitors. Using orthotopic and syngeneic triple negative breast cancer mouse models and treatment with combined AZD6738 and AZD1775 (inhibiting ATR and Wee1, respectively) this study found that: a) Sequential [18F]FLT-PET in the early phase of treatment was able to predict ATR/Wee1 inhibitor treatment efficacy, whereas b) [18F]FLT tumor uptake at onset of therapy was unable to predict treatment outcome, despite c) [18F]FLT tumor uptake positively correlating with Ki-67 staining, the clinically used proliferation marker. Importantly, non-invasive monitoring of changes in tumor biology by [18F]FLT-PET predicted which tumor model responds to combined AZD6738/AZD1775 treatment and established a quantitative correlation in [18F]FLT tumor uptake with tumor shrinkage in individual responders. Since the inhibitors AZD6738 and AZD1775 are already in phase I/II clinical trials, this knowledge could soon be translated into the clinic. To our knowledge this is the first study to correlate non-invasive PET imaging with treatment efficacy of DDR inhibitors. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=100 SRC="FIGDIR/small/710900v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@1e18b7eorg.highwire.dtl.DTLVardef@8d306corg.highwire.dtl.DTLVardef@1663a21org.highwire.dtl.DTLVardef@7261c2_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2026

Answering clinicians' questions over trial evidence tables with verifiable, feedback-driven language models

Systematic reviews condense clinical trials into evidence tables, yet clinicians can interrogate these tables only through database queries, and many questions concern attributes that the table does not record, such as a drug's target class or a harmonised endpoint. Here we introduce FD-SCoPE, a language-model framework that answers both kinds of question, exposes the query, the selected trials and the derivation rule behind every answer, and learns from expert corrections. On an oncology evidence table of 159 immune checkpoint inhibitor trial records, FD-SCoPE completed all 140 clinician-style tasks (alternatives, 90.7--97.9%). For questions needing derived attributes it retrieved 99.3% of relevant trial records at a positive predictive value of 89.8% and outperformed four alternative approaches (derived-value F1 77.7% versus 64.8--73.4%). Corrections on 299 questions, simulated from reference answers, raised F1 on 1,201 unseen questions from 77.9% to 84.9%. Language models coupled with executable queries, verified programs and expert feedback can give clinicians auditable access to trial evidence.

bioengineering↗

bioRxiv2016

Using simulation to aid trial design: ring-vaccination trials

BackgroundThe 2014-5 West African Ebola epidemic highlights the need for rigorous, rapid clinical trials under difficult circumstances. Challenges include temporally and spatially patchy transmission, and the responsibility to deliver public health interventions during a randomized trial. An innovative design such as ring vaccination with an immediate arm and a delayed arm can address these issues, but complex trials raise complex analysis issues.\n\nMethods and FindingsWe present a stochastic, compartmental model for a ring vaccination trial of a vaccine for an Ebola-like disease. After identification of an index case, a ring of primary contacts is recruited and either vaccinated immediately or after a delay of 21 days. The primary outcome of the trial is effectiveness calculated from cumulative incidence in the two arms, counting cases only from a pre-specified window in which the immediate arm is assumed to be fully protected and the delayed arm is not protected. The results of simulating the trial are used to calculate the sample size necessary for 80% power and the estimates of effectiveness are reported under a variety of assumptions regarding the trial design and implementation.\n\nThe three key components of sample size calculations - attack rate in controls, estimate of incidence difference between the arms, and intracluster correlation coefficient - are dependent on trial design and implementation in a way that can be quantitatively predicted by the model. Under baseline parameter assumptions, we found that a total of 8,900 study participants were needed to achieve 80% power to detect a difference in attack rate between the two arms, whereas a standard approach with the same parameters returns a necessary sample size of 7,100 individuals. Such a study would on average return a vaccine effectiveness estimate of 69.81%, with average 95% confidence interval (41.2%, 84.2%).\n\nWe found that for this design the necessary sample size and estimated effectiveness are sensitive to properties of the vaccine - in particular, pre-exposure and post-exposure efficacy; to two setting-specific parameters over which investigators have little control - rate of infections from outside the ring and overall attack rate in the controls; and to three parameters that are determined by the study design - the time window in which cases are counted, intensity of case-detection and administrative delay in vaccinating individuals.\n\nThis approach replaces assumptions about parameters in the trial with assumptions about disease dynamics and vaccine characteristics at the individual level.\n\nConclusionsIncorporating simulation into the trial design process can improve robustness of sample size calculations. Simulation can identify optimal values for study design parameters that can be controlled. For this specific trial design, vaccine effectiveness depends on properties of the ring vaccination design and on the measurement window, as well as the epidemiologic setting. Rejecting the null likely indicates one or more types of vaccine efficacy at the individual level, but the magnitude of the effect will vary across settings.

Epidemiology↗

bioRxiv2020

Preclinical evaluation of Imatinib does not support its use as an antiviral drug against SARS-CoV-2

Following the emergence of SARS-CoV-2, the search for an effective and rapidly available treatment was initiated worldwide based on repurposing of available drugs. Previous reports described the antiviral activity of certain tyrosine kinase inhibitors (TKIs) targeting the Abelson kinase 2 against pathogenic coronaviruses. Imatinib, one of them, has more than twenty years of safe utilization for the treatment of hematological malignancies. In this context, Imatinib was rapidly evaluated in clinical trials against Covid-19. Here, we present the pre-clinical evaluation of Imatinib in multiple models. Our results indicated that Imatinib and another TKI, the Masitinib, exhibit an antiviral activity in VeroE6 cells. However, Imatinib was inactive in a reconstructed bronchial human airway epithelium model. In vivo, Imatinib therapy failed to impair SARS-CoV-2 replication in a golden Syrian hamster model despite high concentrations in plasma and in the lung. Overall, these results do not support the use of Imatinib and similar TKIs as antivirals in the treatment of Covid-19.

microbiology↗

bioRxiv2021

Patient-Derived Three-Dimensional Cortical Neurospheres to Model Parkinson's Disease

There are currently no preventive or disease-modifying therapies for Parkinsons Disease (PD). Failures in clinical trials necessitate a re-evaluation of existing pre-clinical models in order to adopt systems that better recapitulate underlying disease mechanisms and better predict clinical outcomes. In recent years, models utilizing patient-derived induced pluripotent stem cells (iPSCs) have emerged as attractive models to recapitulate disease-relevant neuropathology in vitro without exogenous overexpression of disease-related pathologic proteins. Here, we utilized iPSCs derived from patients with early-onset PD and dementia phenotypes that harbored either a point mutation (A53T) or multiplication at the -synuclein/SNCA gene locus. We generated a three-dimensional (3D) cortical neurosphere culture model to better mimic the tissue microenvironment of the brain. We extensively characterized the differentiation process using quantitative PCR, Western immunoblotting and immunofluorescence staining. Differentiation and aging of the neurospheres revealed alterations in fatty acid profiles and elevated total and pathogenic phospho--synuclein levels in both A53T and the triplication lines compared to their isogenic control lines. Furthermore, treatment of the neurospheres with a small molecule inhibitor of stearoyl CoA desaturase (SCD) attenuated the protein accumulation and aberrant fatty acid profile phenotypes. Our findings suggest that the 3D cortical neurosphere model is a useful tool to interrogate targets for PD and amenable to test small molecule therapeutics.

neuroscience↗

bioRxiv2021

Mitochondrial Dysfunction is a Driver for SP-2509 Drug Resistance in Ewing Sarcoma

Expression of the fusion oncoprotein EWS/FLI causes Ewing sarcoma, an aggressive pediatric tumor characterized by widespread epigenetic deregulation. These epigenetic changes are targeted by novel lysine specific demethylase-1 (LSD1) inhibitors, which are currently in early phase clinical trials. Single agent targeted therapy often induces resistance, and successful clinical development requires knowledge of resistance mechanisms, enabling the design of effective combination strategies. Here, we used a genome-scale CRISPR-Cas9 loss-of-function screen to identify genes whose knockout (KO) conferred resistance to the LSD1 inhibitor SP- 2509 in Ewing sarcoma cell lines. Multiple genes required for mitochondrial electron transport chain (ETC) complexes III and IV function were hits in our screen. We validated this finding using genetic and chemical approaches including CRISPR KO, ETC inhibitors, and mitochondrial depletion. Further global transcriptional profiling revealed that altered complex III/IV function disrupted the oncogenic program mediated by EWS/FLI and LSD1 and blunted the transcriptomic response to SP-2509. These findings demonstrate that mitochondrial dysfunction modulates SP-2509 efficacy and suggest that new therapeutic strategies combining LSD1 with agents which prevent mitochondrial dysfunction may benefit patients with this aggressive malignancy.

cancer biology↗

bioRxiv2022

Extending the Boundaries of Cancer Therapeutic Complexity with Literature Data Mining

Drug combination therapy is a main pillar of cancer therapy but the formation of an effective combinatorial standard of care (SOC) can take many years and its length of development is increasing with complexity of treatment. In this paper, we develop a path to extend the boundaries of complexity in combinatorial cancer treatments using text data mining (TDM). We first use TDM to characterize the current boundaries of cancer treatment complexity and find that the current complexity limit for clinical trials is 6 drugs per plan and for pre-clinical research is 10. We then present a TDM based assistive technology, cancer plan builder (CPB), which we make publicly available and allows experts to create literature-anchored high complexity combination treatment (HCCT) plans of significantly larger size. We develop metrics to evaluate HCCT plans and show that experts using CPB are able to create HCCT plans at much greater speed and quality, compared to experts without CPB. We hope that by releasing CPB we enable more researchers to engage with HCCT planning and demonstrate its clinical efficacy.

bioinformatics↗

bioRxiv2023

Efficient inhibition of fusion inhibitor HY3000 peptide to SARS-CoV-2 emerging EG.5, EG.5.1 and BA.2.86 variants

SARS-CoV-2 continues to evolve and spread. Recently, the Omicron EG.5 lineage, bearing an additional F456L mutation in spike (S) protein compared to its ancestor XBB.1.9.2, and its sub-variant EG.5.1, which carries a further Q52H mutation, have raised concerns due to their increased prevalence and extended immune escape properties. Additionally, an alarming variant, BA.2.86, has also garnered global concern because it contains over 30 amino acid mutations in its S protein compared to BA.2, including more than 10 changes in receptor-binding domain (RBD), reminiscent of the appearance of the Omicron variant in late 2021. Therefore, there is an urgent need to assess the effectiveness of current vaccines and therapeutics against EG.5, EG.5.1 and BA.2.86. In our previous work, we reported the design and broad-spectrum antiviral activity of a peptide fusion inhibitor HY3000 against SARS-CoV-2 and its variants including XBB.1.5. Here, we continued to evaluate the inhibitory potency of the HY3000 peptide against the prevailing EG.5 and EG.5.1, as well as XBB.1.16, FL.1.5.1, FY.3 and BA.2.86. Our data indicated that the peptide retained its potent inhibitory activities against these variants, indicating its potential as a good virus fusion inhibitor with broad-spectrum therapeutic effect against current and future SARS-CoV-2 variants. Currently, the HY3000 has been finished in Phase II clinical trial in China and has also been approved to conduct clinical investigation by U.S. Food and Drug Administration (FDA), suggesting a good application prospect against the ongoing COVID-19.

microbiology↗

bioRxiv2025

Selection of a Lead Long-Acting Formulation of Ivermectin to Target Major Malaria Vectors in Western Africa: Evaluation of Pharmacokinetics and Mosquitocidal Efficacy in Cattle under Laboratory Conditions.

BackgroundIvermectin, a semisynthetic endectocide, is widely used against parasitic nematodes in humans and animals. Its lethality to Anopheles mosquitoes after feeding on treated hosts represents a promising malaria control strategy, particularly against outdoor transmission. However, standard oral formulations for use in humans produce short-lived mosquitocidal blood concentrations, limiting epidemiological impact. To meet WHO Preferred Product Characteristics (PPC) for endectocides against malaria vectors (Hazard Ratios >4 for at least one month), three long-acting injectable ivermectin formulations (LAIFs) based on BEPO(R) depot technology were developed and compared in cattle to identify the most suitable candidate for future human use. MethodsA cattle-Anopheles model was used under laboratory conditions in Bobo-Dioulasso, Burkina Faso. Three LAIF candidates (mdc-STM-001, mdc-STM-002, mdc-STM-003) were injected to calves (n=5 per formulation) at 0.6 mg/kg, with untreated calves as controls (n=5). Plasma ivermectin concentrations were measured over 130 days and analyzed using non-compartmental pharmacokinetics. Direct skin feeding assays were conducted at 15 timepoints (days 2-126 post-injection) using insecticide-susceptible (KIS) and wild-derived resistant (VK5) Anopheles colonies. Efficacy was assessed through 10-day cumulative mortalities, hazard ratios, 50% lethal concentrations (LC50), and duration of exposure above the 10-day LC50, accounting for the extrinsic incubation period of Plasmodium falciparum. ResultsAll formulations were well tolerated. Mdc-STM-001 showed the most favorable pharmacokinetic profile, with a controlled peak concentration (Cmax = 34.5 {+/-} 12.7 ng/mL) and the lowest inter-individual variability (12%). Ten-day hazard ratios exceeded 4 and cumulative mortalities were >50% for at least 60 days in both strains. Median mosquito lifespan remained below 10 days for at least 90 days post-injection. The 10-day LC50 for resistant mosquitoes (3.66 [2.69-4.97] ng/mL) was maintained for [≥]126 days. ConclusionThe Mdc-STM-001 was identified as the optimal candidate. A single injection induced sustained mosquitocidal efficacy for at least two months, achieving HR >4 against both susceptible and resistant Anopheles populations and meeting WHO PPC for malaria endectocides. Although extrapolation from cattle to humans requires caution, the favorable pharmacokinetic profile and robust entomological outcomes support progression to Phase 1 clinical trials. Ivermectins established safety record further strengthens the rationale for clinical development.

pathology↗

bioRxiv2017

Targeting stromal remodeling and cancer stem cell plasticity to overcome chemoresistance in triple negative breast cancer

The cellular and molecular basis of stromal cell recruitment, activation and crosstalk in carcinomas is poorly understood, limiting the development of targeted anti-stromal therapies. In mouse models of triple negative breast cancer (TNBC), Hh ligand produced by neoplastic cells reprogrammed cancer-associated fibroblast (CAF) gene expression, driving tumor growth and metastasis. Hh-activated CAFs upregulated expression of FGF5 and production of fibrillar collagen, leading to FGFR and FAK activation in adjacent neoplastic cells, which then acquired a stem-like, drug-resistant phenotype. Treatment with smoothened inhibitors (SMOi) reversed these phenotypes. Stromal treatment of TNBC patient-derived xenograft (PDX) models with SMOi downregulated the expression of cancer stem cell markers and sensitized tumors to docetaxel, leading to markedly improved survival and reduced metastatic burden. In the phase I clinical trial EDALINE, 3 of 12 patients with metastatic TNBC derived clinical benefit from combination therapy with the SMOi Sonidegib and docetaxel chemotherapy, with one patient experiencing a complete response. Markers of pathway activity correlated with response. These studies identify Hh signaling to CAFs as a novel mediator of cancer stem cell plasticity and an exciting new therapeutic target in TNBC.\n\nSIGNIFICANCECompared to other breast cancer subtypes, TNBCs are associated with significantly worse patient outcomes. Standard of care systemic treatment for patients with non-BRCA1/2 positive TNBC is cytotoxic chemotherapy. However, the failure of 70% of treated TNBCs to attain complete pathological response reflects the relative chemoresistance of these tumors. New therapeutic strategies are needed to improve patient survival and quality of life. Here, we provide new insights into the dynamic interactions between heterotypic cells within a tumor. Specifically, we establish the mechanisms by which CAFs define cancer cell phenotype and demonstrate that the bidirectional CAF-cancer cell crosstalk can be successfully targeted in mice and humans using anti-stromal therapy.

cancer biology↗

bioRxiv2019

OncoOmics approaches to reveal essential genes in breast cancer: a panoramic view from pathogenesis to precision medicine

Breast cancer (BC) is a heterogeneous disease where each OncoOmics approach needs to be fully understood as a part of a complex network. Therefore, the main objective of this study was to analyze genetic alterations, signaling pathways, protein-protein interaction networks, protein expression, dependency maps and enrichment maps in 230 previously prioritized genes by the Consensus Strategy, the Pan-Cancer Atlas, the Pharmacogenomics Knowledgebase and the Cancer Genome Interpreter, in order to reveal essential genes to accelerate the development of precision medicine in BC. The OncoOmics essential genes were rationally filtered to 144, 48 (33%) of which were hallmarks of cancer and 20 (14%) were significant in at least three OncoOmics approaches: RAC1, AKT1 CCND1, PIK3CA, ERBB2, CDH1, MAPK14, TP53, MAPK1, SRC, RAC3, PLCG1, GRB2, MED1, TOP2A, GATA3, BCL2, CTNNB1, EGFR and CDK2. According to the Open Targets Platform, there are 111 drugs that are currently being analyzed in 3151 clinical trials in 39 genes. Lastly, there are more than 800 clinical annotations associated with 94 genes in BC pharmacogenomics.

genomics↗

bioRxiv2026

Combined computational and experimental analysis confirm donor-dependent optimization of critical processing parameters for improving mesenchymal stromal cell potency and expansion attributes

Mesenchymal Stromal Cells (MSC) face several heterogeneity challenges hindering clinical and commercial success. Employing a multiple response model, interplay between donor heterogeneity, and critical processing parameters (CPPs), effects on MSC potency and cell expansion attributes were investigated through computed composite attribute scores. Twelve unique CPP combinations were tested in thirteen marrow-derived MSC(M) and five adipose-tissue MSC(AT) training and test datasets, respectively. Donor heterogeneity and select CPP conditions affected a curated gene panel (surrogate for MSC potency); while MSC expansion was primarily influenced by CPPs. Model performances were evaluated against clinical effectiveness data from a previously deployed clinical trial; top-performing model predicted donor rankings coincided with clinical effectiveness data, validating the modeling approach used. Our model predicted that only 8% of tested donors were agnostic to CPPs; a majority (62%) of donors showed CPP-dependent optimal composite quality attributes, with MSC seeding density as a key driver; medium supplementation and oxygen preferences were highly donor dependent. Approximately 30% of donors performed poorly at all conditions tested and may be prospectively identified using a subset of genes (TGFB, VEGF, PDCD1LG1, PDCD1LG2, IDO). Model predicted optimal parameters worked for 69% of tested donors, while sub-optimal parameters worked for only 23% of donors and were confirmed in an independent CD14+ macrophage assay. Our integrated computational and experimental framework predictably identified interactive effects of donor heterogeneity and CPP conditions to optimize MSC potency attributes.

bioengineering↗

bioRxiv2016

Pre-Hospital Midazolam for Treatment of Status Epilepticus Before and After the Rapid Anticonvulsant Medication Prior to Arrival Trial (RAMPART): A National Observational Cohort Study

BackgroundImplementation of evidence-based treatment for pre-hospital status epilepticus can improve outcomes. We hypothesized that publication of a pivotal pre-hospital clinical trial (RAMPART), demonstrating superiority of intramuscular midazolam over intravenous lorazepam, altered the national utilization rates of midazolam for pre-hospital treatment of status epilepticus, while upholding its safety and efficacy outside the trial setting.\n\nMethods and FindingsThis is a retrospective, observational cohort study of pre-hospital patient encounters throughout the United States in the National Emergency Medicine Services Information System database, from January 2010 through December 2014. We compared the rates and odds of midazolam use as the first-line treatment for status epilepticus among all adult and pediatric benzodiazepine-treated seizures before and after RAMPART publication (February 2012). Secondary analyses were conducted for rates of airway interventions and rescue therapy, as proxies for safety and efficacy of seizure termination. 156,539 benzodiazepine-treated seizures were identified. Midazolam use increased from 26.1% in January 2010 to 61.7% in December 2014 (difference +35.6%, 95% CI, 32.7%-38.4%). The annual rate of midazolam adoption increased significantly from 5.9% per year to 8.9% per year after the publication of RAMPART (difference +3.0% per year; 95%CI, 1.6%-4.5% per year; adjusted OR 1.24; 95%CI, 1.17-1.32). Overall frequency of rescue therapy and airway interventions changed little after the publication of RAMPART.\n\nConclusionsThese data are consistent with effective, ongoing, but incomplete clinical translation of the RAMPART results. The effects of the trial, however, cannot be isolated. The safety and effectiveness of midazolam for treatment of seizures in prehospital clinical practice appear consistent with trial data, which should encourage continuing increases in utilization.

epidemiology↗

bioRxiv2020

Reliable data collection in participatory trials to assess digital healthcare apps.

The number of digital healthcare mobile apps on the market is increasing exponentially owing to the development of the mobile network and widespread usage of smartphones. However, only a few of these apps have undergone adequate validation. As with many mobile apps, healthcare apps are generally considered safe to use, making them easy for developers and end-users to exchange them in the marketplace. The existing platforms are not suitable to collect reliable data for evaluating the effectiveness of the apps. Moreover, these platforms only reflect the perspectives of developers and experts, not of end-users. For instance, data collection methods typical of clinical trials are not appropriate for participant-driven assessment of healthcare apps because of their complexity and high cost. Thus, we identified a need for a participant-driven data collection platform for end-users that is interpretable, systematic, and sustainable --as a first step to validate the effectiveness of the apps. To collect reliable data in the participatory trial format, we defined distinct stages for data preparation, storage, and sharing. Interpretable data preparation consists of a protocol database system and semantic feature retrieval method to create a protocol without professional knowledge. Collected data reliability weight calculation belongs to the systematic data storage stage. For sustainable data collection, we integrated the weight method and the future reward distribution function. We validated the methods through statistical tests conducted on 718 human participants. The validation results demonstrate that the methods have significant differences in the comparative experiment and prove that the choice of the right method is essential for reliable data collection. Furthermore, we created a web-based system for our pilot platform to collect reliable data in an integrated pipeline. We validate the platform features with existing clinical and pragmatic trial data collection platforms. In conclusion, we show that the method and platform support reliable data collection, forging a path to effectiveness validation of digital healthcare apps.

bioinformatics↗

bioRxiv2025

LOX inhibition disrupts a collagen-integrin-MYC axis as a translatable targeting strategy in invasive lobular carcinoma

Invasive lobular carcinoma (ILC) accounts for 15% of breast cancers yet lacks specific therapy because ILCs are underrepresented in clinical trials and preclinical models are lacking. We established intraductal xenograft models to test whether the clinical pan-lysyl-oxidase PXS-5505, now in phase trials for myelofibrosis can exploit the collagen-rich matrix dependency created by CDH1 loss. PXS-5505 remodels fibrillar collagen, and halts tumor expansion and metastatic seeding across ER+ and triple negative models without systemic toxicity. Genome-wide CRISPR screens reveal ITGAV and ITGB5 as synthetic lethal partners of CDH1 and LOX inhibition downregulates their expression together with MYC, NF-{kappa}B, and AP-1 transcriptional programmes. Collagen fibre density/alignment, and MYC/AP-1 gene signatures serve as pharmacodynamic readouts of drug activity. These data uncover a tractable ECM-integrin-MYC axis in ILC and nominate PXS-5505, alone or with endocrine therapy, for window of opportunity trials in this understudied breast cancer subtype. One Sentence SummaryTargeting matrix remodelling in ILC inhibits ILC progression and alters multiple molecular endpoints, providing a translatable therapeutic strategy for this understudied subtype that requires better treatments.

cancer biology↗