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bioRxiv2022

Immature human engineered heart tissues engraft in a guinea pig chronic injury model

AO_SCPLOWBSTRACTC_SCPLOWEngineered heart tissue (EHT) transplantation represents an innovative, regenerative approach for heart failure patients. Late preclinical trials are underway, and the first clinical trial has started in 2021. Preceding studies revealed functional recovery after implantation of in vitro-matured EHT in the subacute stage while transplantation in a chronic injury setting was less efficient. We hypothesized that the use of immature EHT patches (EHTIm) could improve cardiomyocytes (CM) engraftment. Chronic myocardial injury was induced in a guinea pig model (n=14). EHTIm (15x106 cells) were transplanted directly after casting. Functional consequences were assessed by serial echocardiography. Animals were sacrificed four weeks after transplantation and hearts were excised for histological analysis. Cryo-injury lead to large transmural scars amounting to 26% of the left ventricle. Grafts were identified by a positive staining for human Ku80 and dystrophin, remuscularizing 9% of the scar area on average. The CM density in the graft was higher compared to previous studies with in vitro-matured EHTs and showed a greater population of immature CM. Echocardiographic analysis showed a small improvement of left ventricular function after EHTIm transplantation. In a small translational proof-of-concept study human scale EHTIm patches (4.5x108 cells) were epicardially implanted on healthy pig hearts (n=2). In summary, we provide evidence that transplantation of immature EHT patches without pre-cultivation results in better cell engraftment.

pharmacology and toxicology↗

bioRxiv2023

The Antitumor Activities of Anti-CD47 Antibodies Require Fc-FcγR interactions

While anti-CD47 antibodies hold promise for cancer immunotherapy, early phase clinical trials have shown limited signs of clinical benefit, suggesting that blockade of CD47 alone may not be sufficient for effective tumor control. Here, we investigate the contributions of the Fc domain of anti-CD47 antibodies required for optimal in vivo antitumor activity across multiple species-matched models, providing new insights into the mechanisms underlying the efficacy of this emerging class of therapeutic antibodies. Using a novel mouse model humanized for CD47, SIRP and Fc{gamma}Rs, we demonstrate that local administration of an Fc-engineered anti-CD47 antibody with enhanced binding to activating Fc{gamma}Rs modulates myeloid and T-cell subsets in the tumor microenvironment, resulting in improved long-term systemic antitumor immunity and minimal on-target off-tumor toxicity. Our results highlight the importance of Fc optimization in the development of effective anti-CD47 therapies and provide a novel approach for enhancing the antitumor activity of this promising immunotherapy. Highlights- Engagement of activating Fc{gamma}Rs augments the in vivo antitumor activity of CD47 blocking antibodies - Humanized mice for CD47, SIRP and Fc{gamma}Rs allow assessment of hFc{gamma}Rs contribution to the activity of anti-hCD47 Abs - Fc-optimized anti-hCD47 ab promotes systemic antitumor immunity with abscopal effect and minimal on-target toxicity Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=158 SRC="FIGDIR/small/547082v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@1c25202org.highwire.dtl.DTLVardef@960e84org.highwire.dtl.DTLVardef@1930edforg.highwire.dtl.DTLVardef@1b58fcd_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

Stem Cell Secretomes from Surgical Waste: A Novel Approach to Cancer Therapy : An In Vitro Study

IntroductionCancer is the second leading cause of mortality in India, with conventional chemotherapy often limited by drug resistance, off-target toxicity, and metastasis promotion. These treatments indiscriminately attack rapidly dividing cells, including healthy tissues and immune cells, leading to severe side effects and weakened antitumor immunity. Hence, alternative strategies are needed to selectively target cancer cells while minimizing collateral damage. MethodsMesenchymal stem cells (MSCs) were isolated, cultured up to passage 4 (P4), and characterized via flow cytometry and immunocytochemistry for stemness markers. Their differentiation potential was validated using adipogenic and chondrogenic lineage assays. The MSC-derived secretome, collected under hypoxic conditions, was analyzed for its cytotoxic effects on cancer cells using MTT, TMRM staining, and scratch assays. NanoLC-MS/MS profiling and STRING-DB analysis identified key proteins involved in apoptosis, tumor suppression, and DNA damage response. ResultsP2 secretomes exhibited the highest protein concentration and strongest cytotoxic effects. UCSC-derived secretomes showed superior anti-cancer activity, significantly reducing cancer cell viability, mitochondrial membrane potential, and migration. Dose-dependent studies revealed up to 95% cancer cell death with UCSC secretome, while ADSC secretome achieved 80%. In contrast, HEK293-derived secretomes had minimal effects. LC-MS profiling identified tumor-suppressive and apoptosis-inducing proteins, with unique protein signatures distinguishing UCSC and ADSC secretomes. STRING analysis mapped key regulatory pathways in tumor inhibition. ConclusionMSC-derived secretomes, particularly from UCSCs, effectively target aggressive breast cancer cells while sparing normal cells, offering a promising alternative to conventional therapies. Future research should optimize secretome formulations, identify key bioactive components, and validate their efficacy in in vivo models and clinical trials to advance this therapy toward clinical applications.

cell biology↗

bioRxiv2025

Statistical Methods for Binary Outcomes Adjusting for Outcome Dependent Sampling in Longitudinal Studies with Nonignorable Dropout

1.Longitudinal clinical trials and cohort studies often collect clinical data paired with stored biospecimens. An increasing focus of biomedical research is aimed at leveraging these existing specimens to address new research questions. When a hypothesis of interest proposes to utilize costly, limited or difficult to obtain samples, it may not be possible or desirable to assay all samples. In these situations informed sampling strategies (ISS) can be used to minimize costs and preserve biospecimens by providing a framework to select a subset of subjects that is more informative than a simple random sample. The samples from selected subjects can be assayed and the resulting data can be analyzed in concert with an analytical correction. Dropout is common in longitudinal studies but existing ISS methods do not address nonignorable dropout. Ignoring cases where poor outcomes may influence the propensity to dropout could bias study results. We propose an expansion of current ISS frameworks to account for nonignorable dropout. Mixture models, commonly used to adjust for dropout, are modified to accommodate analysis of data from ISS designs. Methods are available in the BUILD R package.

bioinformatics↗

bioRxiv2019

Pool walking may temporarily improve renal function by suppressing renin-angiotensin-aldosterone system in pregnant women

BackgroundThis study aimed to examine the effect of pool walking on renal function in pregnant women. MethodsFifteen pregnant women (mean gestational age, 37.8 weeks) walked in a pool (depth 1.3 m) for 1 h. A few days later, they walked on a street for 1 h. Within each activity, the starting and ending levels of plasma renin activity (PRA) and serum aldosterone (SA) were compared using paired t-test. Total urine volume, creatinine clearance, and change in PRA levels between each activity were compared by t-test. Regression coefficients for total urine volume and creatinine clearance during pool walking were estimated by linear regression and additionally controlled for the change in PRA levels. Land walking served as the reference group. ResultsWithin each activity, the renin-angiotensin-aldosterone levels were suppressed during pool walking: the mean starting and ending values of PRA and SA were 6.8 vs. 5.5 ng/mL/h (p=0.002) and 654 vs. 473 pg/mL (p=0.02), respectively. Compared to land walking, the decrease in PRA level was more evident in pool walking (-1.27 vs. 0.81 ng/mL/h, p=0.004), resulting in higher total urine volume and creatinine clearance in pool walking (both p<0.05). In regression analysis, after controlling for the change in PRA levels, the significantly elevated regression coefficients for total urine volume and creatinine clearance in pool walking were attenuated. ConclusionsPool walking may temporarily improve renal function in pregnant women, partly through the suppressed renin-angiotensin-aldosterone system. Clinical Trial RegistrationURL: https://upload.umin.ac.jp/cgi-bin/ctr/ctr_view_reg.cgi?recptno=R000010618 Unique Identifier: UMIN000009051

clinical trials↗

bioRxiv2018

Exploratory analyses suggest less cognitive decline on nilvadipine treatment in very mild Alzheimer’s disease subjects

BackgroundWe explored whether the effects of nilvadipine on cognition were influenced by baseline Alzheimers disease (AD) severity.\n\nMethodsExploratory analyses were performed on the modified intention-to-treat (mITT) dataset (n = 497) of a phase III randomized placebo-controlled trial to examine the response to nilvadipine in very mild, mild and moderate AD subjects. The outcome measures included total and subscale scores of the Alzheimers Disease Assessment Scale Cognitive 12 (ADAS-Cog 12), the Clinical Dementia Rating Scale sum of boxes (CDR-sb) and the AD composite score (ADCOMS), an outcome measure recently developed to detect treatment responses in subjects with prodromal AD. Cerebrospinal fluid (CSF) biomarkers A{beta}38, A{beta}40, A{beta}42, total tau and P181 tau were measured in a subset of samples (n = 55). Regression analyses were adjusted for potential confounders and effect modifiers in order to examine the interactive effects of nilvadipine and AD severity on cognitive outcomes over 78-weeks.\n\nResultsCompared to their respective placebo-controls, nilvadipine-treated, very mild AD subjects showed less decline, whereas moderate AD subjects showed greater decline on the ADAS-Cog 12. Also in very mild AD, a beneficial effect (as measured by ADCOMS), was detected in the nilvadipine treated group. Therapeutic effects of nilvadipine were also observed for a composite memory trait in very mild AD subjects and a composite language trait in mild AD subjects. CSF A{beta}42/A{beta}40 ratios were increased in mild AD and decreased in moderate AD patients treated with nilvadipine, compared to their respective controls.\n\nConclusionThese data suggest that very mild AD subjects benefited from nilvadipine and that future clinical trials of nilvadipine in this population are required to confirm these findings.\n\nTrial RegistrationNCT02017340 Registered 20 December 2013, https://clinicaltrials.gov/ct2/show/NCT02017340\n\nEUDRACT Reference Number 2012-002764-27 Registered 04 February 2013, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2012-002764-27

clinical trials↗

bioRxiv2025

Development of a Time-based Drug Screening Platform for Improved Clinical Translation

In 2022, the average cost for a single drugs development increased by 15%, reaching $2.3 billion. In drug development, oncology has the highest attrition rate with 95% of new drugs failing Phase 2 clinical trials alone. Consequently, innovative approaches are needed to assess clinical utility prior to proceeding with human trials. Current drug development follows the theory that "Best Potency = Best Drug" which is a concentration-centric paradigm focused on optimizing drug-target interaction (Kd) to improve the concentration of drug necessary to elicit its therapeutic effect (IC50). However, both drug concentration and exposure time contribute to clinical efficacy, yet most laboratory studies focus on IC50 alone. This manuscript characterizes drug potency and kinetics of ten oncology drugs in three different cancer cell lines and integrates in vivo pharmacokinetic-pharmacodynamic models to identify how these parameters relate to real-world clinical outcomes. Our analyses revealed that Cmax normalization is necessary for concentration response data as IC50 alone does not account for drugs that are studied at sub-therapeutic concentrations. Additionally, the temporal effect of drug efficacy varies between cell lines and dose, where some drugs are unable to overcome the proliferation rate of the cells to induce a decrease in disease progression. This work aims to enhance the design and implementation of drug regimens by understanding the time-dependence of clinical efficacy and cytotoxicity.

pharmacology and toxicology↗

bioRxiv2022

Breakthrough: A First-In-Class Virtual Simulator for Dose Optimization of ACE Inhibitors in Veterinary Cardiology

AO_SCPLOWBSTRACTC_SCPLOWThe human and canine renin-angiotensin-aldosterone-systems (RAAS) play a central role in the pathophysiology of congestive heart failure (CHF), justifying the use of angiotensin converting enzyme inhibitors inhibitors (ACEi) in this indication. Seminal studies in canine CHF had suggested that the pharmacological action of benazepril was relatively independent of doses > 0.25 mg/kg P.O, thereby providing a rationale for the European label dose of 0.25 mg/kg P.O q24h in dogs with cardiovascular diseases. However, most of these earlier studies on benazepril pharmacodynamics relied on measures of ACE activity - a sub-optimal endpoint to characterize the effect of benazepril on the RAAS. Nonlinear mixed-effects (NLME) modeling is an established framework for characterizing the effect of therapeutics on complex biological systems, such as the RAAS cascade. Importantly for therapeutic schedule optimization, one can use such a model to predict the outcomes of various hypothetical dosing schedules via simulation. The objectives of this study were (i) to expand on previous NLME modeling efforts of the dose-exposure-response relationship of benazepril on biomarkers of the RAAS which are relevant to CHF pathophysiology and disease prognosis {angiotensins I, II, III, IV, (1-7)} by using a quantitative systems pharmacology (QSP) modeling approach; and (ii) to develop a software implementation of the model capable of simulating clinical trials in benazepril in dogs bedside dose optimization. This study expands on previous modeling efforts to characterize the changes in RAAS pharmacodynamics in response to benazepril administration and showcase how QSP modeling can be used for efficient dose optimization of ACEis at the bedside. Our results suggest that 0.5 mg/kg PO q12h of benazepril produced the most robust reduction in AngII and upregulation of RAAS alternative pathway biomarkers. This model will eventually be expanded to include relevant clinical endpoints, which will be evaluated in an upcoming prospective trial in canine patients with CHF. AO_SCPLOWUTHORC_SCPLOW SO_SCPLOWUMMARYC_SCPLOWCongestive heart failure (CHF) is a disease of the heart, common to both dogs and humans, where the heart is not healthy enough to pump blood around the body efficiently. Because the blood isnt moving around the body as efficiently, it tends to get congested in various areas of the body and increases strain on the heart. Benazepril is a drug for CHF used in both dogs and humans to reduce congestion and improve the functioning of the cardiovascular system. Although benazepril is effective, theres evidence that suggests the dosing could be improved if the therapeutic was further studied. In this experiment, we tested benazepril at several safe dosages in well-cared for and healthy dogs to collect data on the relationship between dose size, dosing frequency, and effect on the cardiovascular system. Using this data, we built computer models of benazepril to simulate many clinical trials. By studying these simulations, we were able to make several predictions about the optimal dosing schedule of benazepril in dogs. Weve also built a web-app version of the computer model for veterinary researchers to use, modify, and study. This work also provides a platform and roadmap for optimizing benazepril dosages in human CHF.

pharmacology and toxicology↗

bioRxiv2026

Differential effects of two common GVHD prophylaxis regimens on the gut microbiome: Results from the BMT CTN 1801 study

Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment for many hematological malignancies, but graft-versus-host disease (GVHD) is a common complication. Low gut microbiome diversity is associated with higher GVHD risk and shorter survival in multiple studies. Recently, the BMT CTN 1703 clinical trial demonstrated superiority of a GVHD-prophylaxis regimen including post-transplant cyclophosphamide (PTCy) compared to the standard prophylaxis (tacrolimus and methotrexate, Tac/MTX) in terms of GVHD-free, relapse-free survival at one year among reduced intensity conditioning allo-HCT recipients. However, the effect of PTCy on the gut microbiome and its association with clinical outcome have not been described. Here, we report on a companion randomized clinical controlled trial (BMT CTN 1801), which collected 2575 longitudinal stool samples from 304 study participants. Samples were obtained up to weekly up to day 84 post allo-HCT and at less frequent intervals thereafter, up to 2 years. Microbiome diversity and absolute microbial load were lower in the PTCy group compared to the Tac/MTX group on days 14-28 post-HCT. However, diversity at the timepoint closest to neutrophil engraftment was not significantly associated with non-relapse mortality after one year or other clinical outcomes, contrary to expectations from previous studies. Microbial domination events, when a single species exceeds 30% relative abundance, were comparable across treatment arms and reflected both pathogen blooms as well as less severe disruptions of the microbial community. Clostridium scindens and secondary bile acid metabolism pathways were less prevalent in the PTCy arm than in the Tac/MTX arm post-HCT, yet presence of secondary bile acid metabolism pathways was associated with a lower risk of chronic GVHD. Given that PTCy was associated with a greater disruption of the microbiome as measured by diversity, absolute microbial abundance, and bile acid metabolism capability, but better clinical outcomes overall, these data suggest that the importance of the microbiome in modulating the host immune systems after allo-HCT is specific to different types of GVHD prophylaxis.

microbiology↗

bioRxiv2016

Chloroquine inhibits Zika Virus infection in different cellular models

Zika virus (ZIKV) infection in utero might lead to microcephaly and other congenital defects. In adults, cases of Guillain-Barre syndrome and meningoencephalitis associated with ZIKV infection have been reported, and no specific therapy is available so far. There is urgency for the discovery of antiviral agents capable of inhibiting viral replication and its deleterious effects. Chloroquine is widely administered as an antimalarial drug, anti-inflammatory agent, and it also shows antiviral activity against several viruses. Here we show that chloroquine exhibits antiviral activity against ZIKV in VERO, human brain microvascular endothelial, and neural stem cells. We demonstrated in vitro that chloroquine reduces the number of ZIKV-infected cells, virus production and cell death promoted by ZIKV infection without cytotoxic effects. Our results suggest that chloroquine is a promising candidate for ZIKV clinical trials, since it is already approved for clinical use and can be safely administered to pregnant woman.

Microbiology↗

bioRxiv2021

Of Rats and Men, a Translational Model to Understand Vancomycin Pharmacokinetic/Toxicodynamic relationships

BackgroundVancomycin is a first line antibiotic for many common infectious diseases and is the most commonly prescribed antibiotic in the United States hospital setting. Vancomycin is also well known to cause kidney injury; two recent prospective studies have identified that increasing vancomycin area under the concentration curve predicts vancomycin induced kidney injury (VIKI). However, outside of clinical trials, it is unclear if pre-clinical data can quantitatively describe VIKI in patients. MethodsData were simultaneously analyzed from a pre-clinical rat model and two prospective clinical studies. Logged vancomycin area under the concentration curve (AUC) data for rats (n=48) and patients from PROVIDE (n=263) and CAMERA2 (n=291) were included. VIKI was defined as urinary KIM-1 concentrations [≥]9.42 ng/mL in the rat and according to KDIGO stage 1 kidney injury for all human patients. Multiple generalized linear models were explored, and the order of magnitude was calculated between the probability of acute kidney injury (AKI) from the average obtained in the clinical studies (i.e. CAMERA2 and PROVIDE) and the rat for 0.1 increments in Log10AUC bounded common concentrations obtained in the therapeutic range (i.e. ~200 -800 mg*24h/L). ResultsA logit link model best fit the data. When calculating the multiplicative factors between the studies therapeutic range AUCs, the rat was an average 2.7 to 4.2 times more sensitive to AKI between AUCs of 199.5 (i.e. log 10 AUC=2.3) and 794.3 mg*h/L (i.e. log 10 AUC=2.9), respectively. ConclusionsA pre-clinical rat model was quantitatively linked to toxicity data from two large human studies. The rat is an attractive pre-clinical model to explore exposure toxicity relationships with vancomycin. External validation is required.

pharmacology and toxicology↗

bioRxiv2022

Predicting patient treatment response and resistance via single-cell transcriptomics of their tumors

Tailoring the best treatments to cancer patients is an important open challenge. Here, we build a precision oncology data science and software framework for PERsonalized single-Cell Expression-based Planning for Treatments In Oncology (PERCEPTION). Our approach capitalizes on recently published matched bulk and single-cell transcriptome profiles of large-scale cell-line drug screens to build treatment response models from patients single-cell (SC) tumor transcriptomics. First, we show that PERCEPTION successfully predicts the response to monotherapy and combination treatments in screens performed in cancer and patient-tumor-derived primary cells based on SC-expression profiles. Second, it successfully stratifies responders to combination therapy based on the patients tumors SC-expression in two very recent multiple myeloma and breast cancer clinical trials. Thirdly, it captures the development of clinical resistance to five standard tyrosine kinase inhibitors using tumor SC-expression profiles obtained during treatment in a lung cancer patients cohort. Notably, PERCEPTION outperforms state-of-the-art bulk expression-based predictors in all three clinical cohorts. In sum, this study provides a first-of-its-kind conceptual and computational method that is predictive of response to therapy in patients, based on the clonal SC gene expression of their tumors.

bioinformatics↗

bioRxiv2024

Challenges and promises in optimising a non-clinical protocol of intracerebroventricular human neural stem cell transplantation in ALS

Background and aimsNeural stem cell (NSC) transplantation holds promising therapeutic potential for neurodegenerative disorders like amyotrophic lateral sclerosis (ALS). However, pre-clinical studies and early-phase clinical trials have faced challenges hindering the effective clinical translation of this approach. Crucial hurdles include the side-effects of prolonged immunosuppression, concerns regarding cell origin and transplantation dosage, identification of the most appropriate therapeutic window, and invasiveness of surgical procedures. Here, we show challenges and promises in optimizing a non-clinical protocol to assess safety and efficacy of human NSC (hNSC) intracerebroventricular (ICV) transplantation for ALS. MethodsWe evaluated the safety of administering up to 1x106 hNSCs in immunodeficient mice and assessed their potential efficacy in reducing ALS hallmarks employing the SOD1G93A mouse model. Both, transient (15 days) and prolonged immunosuppression regimens, at low (15 mg/kg) and high (30 mg/kg) doses, were tested along with two different cell dosages (3x105 and 1x106). ResultsBilateral ICV injection of up to 1x106 hNSCs proved to be safe, with no evidence of tumor formation. At 40 days post-transplantation, hNSCs induced a trend toward delaying motor decline and reducing spinal cord (SC) microgliosis when transplanted under prolonged high-dose (30 mg/kg) immunosuppression. ConclusionsOur study suggests that: (i) a bilateral ICV transplantation of 1x106 hNSCs is safe and non-tumorigenic in immunodeficient hosts; (ii) sustained high-dose immunosuppression is essential for ensuring cell survival in immunocompetent mice; and (iii) hNSC transplantation may provide therapeutic benefits in ALS by delaying motor decline and reducing microgliosis. This study also highlights persisting hurdles that need to be further addressed, such as the aggressive murine immune response to exogenous cells.

neuroscience↗

bioRxiv2025

Intratumoral expression of IL-12 and CD40 ligand (CD154) from plasmids generates antitumor responses that eliminate tumoral T regs

Intratumoral immunotherapy (ITIT) strives to generate effective antitumor immunity by directly stimulating the immune system in tumors to reverse local tumor-mediated immune suppression. In vivo expression of Interleukin-12 (IL-12) using in vivo plasmid transfection as an intratumoral cancer immunotherapy entered Phase II clinical trials for metastatic melanoma but to limited clinical success. We sought to improve the efficacy of in vivo IL-12 electroporation by the addition of a CD154 (CD40 ligand)- expressing plasmid to the IL-12 encoding plasmid treatment and assessing efficacy against solid tumors. Mice with intradermal B16F10 melanoma or MC38 murine colon carcinoma tumors received 2 weekly intratumoral (IT) injections of plasmids encoding IL-12 and CD154, followed by in vivo electroporation. The addition of CD154 to IL-12 was superior to IL-12 alone and resulted in frequent tumor clearance of treated tumors, marked by an increase in CD8 T cells and a drastic reduction in T regulatory cells in the tumor microenvironment. Tumor treatment responses were abrogated in mice which lack conventional DC1 cells (BatF3 KO) or lack CD8 T cells. These findings highlight the potential of adding CD154 to IL-12 plasmid electroporation as a cancer immunotherapy and suggest that other combinations would be therapeutically valuable.

immunology↗

bioRxiv2025

Sex-specific human electromechanical multiscale in-silico models for virtual therapy evaluation

Background and AimWomen are significantly under-represented in cardiovascular research and in the evaluation of treatment safety and efficacy, leading to poorer patient outcomes. Quantification and investigation of sex differences in human electromechanical function and underlying mechanisms is crucial. To address this, we present sex-specific human cellular and biventricular electromechanical models for mechanistic investigations into sex-differences in therapy evaluation through simulations. MethodsProtein genomic expression data from healthy human myocytes were used to calibrate sex-specific models of human cellular electrophysiology, subsequently integrated in biventricular electromechanical models with male and female anatomies. A validation, verification and uncertainty evaluation were implemented at the cellular and biventricular level, including validation using sex-specific datasets from randomised controlled trials for Dofetilide and Verapamil, with known sex-differences. Ionic mechanisms underlying sex-differences in drug response were mechanistically investigated. ResultsSex-specific electromechanical models recapitulate sex-differences from ionic currents to ECG biomarkers including QTc interval (Male: 312ms; Female: 339ms; 9% difference), T-wave amplitude (6-9% difference) and ST-steepness through electrophysiological changes alone. Sex-specific simulations demonstrate both ECG biomarkers and mechanical biomarkers (Female LVEF: 68%, Male LVEF: 50%) within healthy ranges in clinical data for male and female population in the UK Biobank (n= 806, 46% Male). ECGs sex-differences are primarily explained by ionic currents, whereas mechanical sex-differences are driven by anatomical differences, and secondarily through more robust calcium function in females. Under Dofetilide, simulations show exacerbated QT prolongation in women compared to men (54-78% increase in effect), and a T-wave amplitude decrease in males (up to 0.25 mV), consistent with clinical data. This is explained in simulations by lower repolarisation reserve in women (due to low potassium and high calcium currents) than men. Verapamil shows no effect on simulated QT in either sex, and divergent T-wave modulation (increased amplitude in females, decreased in males) consistent with clinical trial data. Simulations identify enhanced contractile reservoir in female compared to male, with lesser decreases to ejection fraction with calcium current block. ConclusionSimulations using novel, sex-specific cellular and biventricular electromechanical models reveal the primary role of ionic currents sex-differences in ECG and drug response, whereas mechanical sex-differences are also underpinned by anatomical differences. Main ContributionsO_LIDevelopment, calibration and validation of sex-specific human ventricular electromechanical, multiscale models. C_LIO_LIAn analysis of clinical randomised trial data in the context of sex-specific effects of multi-channel blockers on the ECG by dosage, where previous analysis focused on pharmacokinetics. C_LIO_LIConsideration of both sex-specific electrophysiology and anatomy explains sex-specific differences on the impact of drugs on ECG and mechanics. C_LIO_LISimulations demonstrate that the reduced repolarisation reserve in females increases the susceptibility to QTc prolongation via potassium channel block compared to males, and more robust calcium dynamics protect against t-wave amplitude reduction and the more severe contractility loss through L-type calcium inhibition observed in males. C_LI

physiology↗

bioRxiv2018

A double-blinded randomised placebo-controlled phase II trial to evaluate high dose rifampicin for tuberculous meningitis: a dose finding study

BackgroundHigh doses of rifampicin may help tuberculous meningitis (TBM) patients to survive. Pharmacokinetic-pharmacodynamic evaluations suggested that rifampicin doses higher than 13 mg/kg intravenously or 20 mg/kg orally (as previously studied) are warranted to maximize treatment response.\n\nMethodsIn a double-blinded, randomised, placebo-controlled phase II trial, we assigned 60 adult TBM patients in Bandung, Indonesia, to standard 450 mg, 900 mg or 1350 mg (10, 20 and 30 mg/kg) oral rifampicin combined with other TB drugs for 30 days. Endpoints included pharmacokinetic measures, adverse events and survival.\n\nResultsA double and triple dose of oral rifampicin led to three and five-fold higher geometric mean total exposures in plasma in the critical early days (2{+/-}1) of treatment (AUC0-24h: 53{middle dot}5 mg.h/L vs 170{middle dot}6 mg.h/L vs. 293{middle dot}5 mg.h/L, p<0{middle dot}001), with proportional increases in CSF concentrations and without an increase in the incidence of grade 3/4 adverse events. Six-month mortality was 7/20 (35%, 9/20 (45%) and 3/20 (15%) in the 10, 20 and 30 mg/kg groups, respectively (p=0{middle dot}12).\n\nConclusionsTripling the standard dose caused a large increase in rifampicin exposure in plasma and CSF and was safe. Survival benefit with this dose should now be evaluated in a larger phase III clinical trial.

clinical trials↗

bioRxiv2019

PARP1 as a biomarker for early detection and intraoperative tumor delineation in epithelial cancers - first-in-human results

Major determining factors for survival of patients with oral, oropharyngeal, and esophageal cancer are early detection, the quality of surgical margins, and the contemporaneous detection of residual tumor. Intuitively, the exposed location at the epithelial surface qualifies these tumor types for utilization of visual aids to assist in discriminating tumor from healthy surrounding tissue. Here, we explored the DNA repair enzyme PARP1 as imaging biomarker and conducted optical imaging in animal models, human tissues and as part of a first-in-human clinical trial. Our data suggests that PARP1 is a quantitative biomarker for oral, oropharyngeal, and esophageal cancer and can be visualized with PARPi-FL, a fluorescently labeled small molecule contrast agent for topical or intravenous delivery. We show feasibility of PARPi-FL-assisted tumor detection in esophageal cancer, oropharyngeal and oral cancer. We developed a contemporaneous PARPi-FL topical staining protocol for human biospecimens. Using fresh oral cancer tissues within 25 min of biopsy, tumor and margin samples were correctly identified with >95% sensitivity and specificity without terminal processing. PARPi-FL imaging can be integrated into clinical workflows, potentially providing instantaneous assessment of the presence or absence of microscopic disease at the surgical margin. Additionally, we showed first-in-human PARPi-FL imaging in oral cancer. In aggregate, our preclinical and clinical studies have the unifying goal of verifying the clinical value of PARPi-FL-based optical imaging for early detection and intraoperative margin assignment.

clinical trials↗

bioRxiv2024

Profiling microRNA expression during senescence and aging: mining for a diagnostic tool of senescent-cell burden

In the last decade cellular senescence, a hallmark of aging, has come into focus for pharmacologically targeting aging processes. Senolytics are one of these interventive strategies that have advanced into clinical trials, creating an unmet need for minimally invasive biomarkers of senescent cell load to identify patients at need for senotherapy. We created a landscape of miRNA and mRNA expression in five human cell types induced to senescence in-vitro and provide proof-of-principle evidence that miRNA expression can track senescence burden dynamically in-vivo using transgenic p21high senescent cell clearance in HFD fed mice. Finally, we profiled miRNA expression in seven different tissues, total plasma, and plasma derived EVs of young and 25 months old mice. In a systematic analysis, we identified 22 candidate senomiRs with potential to serve as circulating biomarkers of senescence not only in rodents, but also in upcoming human clinical senolytic trials.

molecular biology↗