Making a difference.

This is a personal account of one academic scientist who founded two biotechnology companies. Both companies were initially incubated within the walls of the university under a creative student incubator program whereby biology students could pursue their graduate academic degrees while gaining valuable biotechnology experiences. After the companies transitioned out of the university environment, the professor and his students pursued diagnostic and therapeutic drug development resulting in the completion of several clinical trials.

Cerebrospinal Fluid Levels of Lysophosphatidic Acids Can Provide Suitable Biomarkers of Blast-Induced Traumatic Brain Injury.

Blast-induced traumatic brain injury (bTBI) has been identified as the signature injury of Operation Iraqi Freedom and Operation Enduring Freedom. Although the incidence of bTBI increased significantly after the introduction of improvised explosive devices, the mechanism of the injury is still uncertain, which is negatively impacting the development of suitable countermeasures. Identification of suitable biomarkers that could aid in the proper diagnosis of and prognosis for both acute and chronic bTBI is essential since bTBI frequently is occult and may not be associated with overtly detectable injuries to the head.

Multimodal Finger Pulse Wave Sensing: Comparison of Forcecardiography and Photoplethysmography Sensors.

Pulse waves (PWs) are mechanical waves that propagate from the ventricles through the whole vascular system as brisk enlargements of the blood vessels' lumens, caused by sudden increases in local blood pressure. Photoplethysmography (PPG) is one of the most widespread techniques employed for PW sensing due to its ability to measure blood oxygen saturation. Other sensors and techniques have been proposed to record PWs, and include applanation tonometers, piezoelectric sensors, force sensors of different kinds, and accelerometers.

Pain-like behavior in the collagen antibody-induced arthritis model is regulated by lysophosphatidic acid and activation of satellite glia cells.

Inflammatory and neuropathic-like components underlie rheumatoid arthritis (RA)-associated pain, and lysophosphatidic acid (LPA) is linked to both joint inflammation in RA patients and to neuropathic pain. Thus, we investigated a role for LPA signalling using the collagen antibody-induced arthritis (CAIA) model. Pain-like behavior during the inflammatory phase and the late, neuropathic-like phase of CAIA was reversed by a neutralizing antibody generated against LPA and by an LPA receptor inhibitor, but joint inflammation was not affected.

Probing Allosteric Hsp70 Inhibitors by Molecular Modelling Studies to Expedite the Development of Novel Combined F508del CFTR Modulators.

Cystic fibrosis (CF) is caused by different mutations related to the cystic fibrosis transmembrane regulator protein (CFTR), with F508del being the most common. Pioneering the development of CFTR modulators, thanks to the development of effective correctors or potentiators, more recent studies deeply encouraged the administration of triple combination therapeutics. However, combinations of molecules interacting with other proteins involved in functionality of the CFTR channel recently arose as a promising approach to address a large rescue of F508del-CFTR.

A Wearable System with Embedded Conductive Textiles and an IMU for Unobtrusive Cardio-Respiratory Monitoring.

The continuous and simultaneous monitoring of physiological parameters represents a key aspect in clinical environments, remote monitoring and occupational settings. In this regard, respiratory rate (RR) and heart rate (HR) are correlated with several physiological and pathological conditions of the patients/workers, and with environmental stressors. In this work, we present and validate a wearable device for the continuous monitoring of such parameters.

Antibodies Against Lysophosphatidic Acid Protect Against Blast-Induced Ocular Injuries.

Exposure to blast overpressure waves is implicated as the major cause of ocular injuries and resultant visual dysfunction in veterans involved in recent combat operations. No effective therapeutic strategies have been developed so far for blast-induced ocular dysfunction. Lysophosphatidic acid (LPA) is a bioactive phospholipid generated by activated platelets, astrocytes, choroidal plexus cells, and microglia and is reported to play major roles in stimulating inflammatory processes.

Breath-Jockey: Development and Feasibility Assessment of a Wearable System for Respiratory Rate and Kinematic Parameter Estimation for Gallop Athletes.

In recent years, wearable devices for physiological parameter monitoring in sports and physical activities have been gaining momentum. In particular, some studies have focused their attention on using available commercial monitoring systems mainly on horses during training sessions or competitions. Only a few studies have focused on the jockey's physiological and kinematic parameters.

An fMRI Compatible Smart Device for Measuring Palmar Grasping Actions in Newborns.

Grasping is one of the first dominant motor behaviors that enable interaction of a newborn infant with its surroundings. Although atypical grasping patterns are considered predictive of neuromotor disorders and injuries, their clinical assessment suffers from examiner subjectivity, and the neuropathophysiology is poorly understood. Therefore, the combination of technology with functional magnetic resonance imaging (fMRI) may help to precisely map the brain activity associated with grasping and thus provide important insights into how functional outcomes can be improved following cerebral injury.

A Wearable Device Based on a Fiber Bragg Grating Sensor for Low Back Movements Monitoring.

Low back pain (LBP) is one of the musculoskeletal disorders that most affects workers. Among others, one of the working categories which mainly experiences such disease are video terminal workers. As it causes exploitation of the National Health Service and absenteeism in workplaces, LBP constitutes a relevant socio-economic burden.

A Multi-Parametric Wearable System to Monitor Neck Movements and Respiratory Frequency of Computer Workers.

Musculoskeletal disorders are the most common form of occupational ill-health. Neck pain is one of the most prevalent musculoskeletal disorders experienced by computer workers. Wrong postural habits and non-compliance of the workstation to ergonomics guidelines are the leading causes of neck pain.

Sphingosine-1-phosphate signalling drives an angiogenic transcriptional programme in diffuse large B cell lymphoma.

Although the over-expression of angiogenic factors is reported in diffuse large B-cell lymphoma (DLBCL), the poor response to anti-VEGF drugs observed in clinical trials suggests that angiogenesis in these tumours might be driven by VEGF-independent pathways. We show that sphingosine kinase-1 (SPHK1), which generates the potent bioactive sphingolipid sphingosine-1-phosphate (S1P), is over-expressed in DLBCL. A meta-analysis of over 2000 cases revealed that genes correlated with SPHK1 mRNA expression in DLBCL were significantly enriched for tumour angiogenesis meta-signature genes; an effect evident in both major cell of origin (COO) and stromal subtypes.

Matrix-Assisted Laser Desorption Ionization Mapping of Lysophosphatidic Acid Changes after Traumatic Brain Injury and the Relationship to Cellular Pathology.

Lysophosphatidic acid (LPA) levels increase in the cerebrospinal fluid and blood within 24 hours after traumatic brain injury (TBI), indicating it may be a biomarker for subsequent cellular pathology. However, no data exist that document this association after TBI. We, therefore, acquired matrix-assisted laser desorption ionization imaging mass spectrometry data of LPA, major LPA metabolites, and hemoglobin from adult rat brains at 1 and 3 hours after controlled cortical impact injury.

Nervous system delivery of antilysophosphatidic acid antibody by nasal application attenuates mechanical allodynia after traumatic brain injury in rats.

Lysophosphatidic acid (LPA) is a bioactive lipid that impacts neurological outcomes after neurotrauma by inhibiting neuroregeneration, promoting inflammation, and contributing to behavioral deficits. Blocking LPA signaling with a novel anti-LPA monoclonal antibody (mAb) is neuroprotective after traumatic brain injury (TBI) if given to injured animals whose blood-brain barrier (BBB) has been compromised. It is hypothesized that the anti-LPA mAb could improve chronic pain initiated by TBI.

Acid ceramidase confers radioresistance to glioblastoma cells.

Glioblastoma multiforme (GBM) is the most common primary, intracranial malignancy of the central nervous system. The standard treatment protocol, which involves surgical resection, and concurrent radiation with adjuvant temozolomide (TMZ), still imparts a grim prognosis. Ultimately, all GBMs exhibit recurrence or progression, developing resistance to standard treatment.

Immunohistochemical Detection of Sphingosine-1-Phosphate and Sphingosine Kinase-1 in Human Tissue Samples and Cell Lines.

Sphingosine-1-phosphate (S1P) and the enzyme primarily responsible for its production, sphingosine kinase-1 (SphK-1), are dysregulated in multiple human diseases including cancer, multiple sclerosis (MS), diabetes, neurological diseases, fibrosis, and certain pathologies associated with impaired angiogenesis such as age-related macular degeneration (AMD). Antibody-based techniques to identify and localize S1P and SphK-1 within cells and tissue specimens represent a powerful tool, not only to understand biological role of these molecules but also to validate these unique in-class targets in multiple state diseases. Consequently, the potential applications of these molecules for therapy and diagnostic purposes are currently under investigation.

Sphingosine 1-phosphate signaling through its receptor S1P promotes chromosome segregation and mitotic progression.

Sphingosine kinase 1 (SphK1) promotes cell proliferation and survival, and its abundance is often increased in tumors. SphK1 produces the signaling lipid sphingosine 1-phosphate (S1P), which activates signaling cascades downstream five G protein-coupled receptors (S1P) to modulate vascular and immune system function and promote proliferation. We identified a new function of the SphK1-S1P pathway specifically in the control of mitosis.

Precise Somatotopic Thalamocortical Axon Guidance Depends on LPA-Mediated PRG-2/Radixin Signaling.

Precise connection of thalamic barreloids with their corresponding cortical barrels is critical for processing of vibrissal sensory information. Here, we show that PRG-2, a phospholipid-interacting molecule, is important for thalamocortical axon guidance. Developing thalamocortical fibers both in PRG-2 full knockout (KO) and in thalamus-specific KO mice prematurely entered the cortical plate, eventually innervating non-corresponding barrels.

Preclinical evaluation of VAX-IP, a novel bacterial minicell-based biopharmaceutical for nonmuscle invasive bladder cancer.

The development of new therapies that can prevent recurrence and progression of nonmuscle invasive bladder cancer remains an unmet clinical need. The continued cost of monitoring and treatment of recurrent disease, along with its high prevalence and incidence rate, is a strain on healthcare economics worldwide. The current work describes the characterization and pharmacological evaluation of VAX-IP as a novel bacterial minicell-based biopharmaceutical agent undergoing development for the treatment of nonmuscle invasive bladder cancer and other oncology indications.

Essential role for SphK1/S1P signaling to regulate hypoxia-inducible factor 2α expression and activity in cancer.

The sphingosine kinase-1/sphingosine 1-phosphate (SphK1/S1P) signaling pathway has been reported to modulate the expression of the canonical transcription factor hypoxia-inducible HIF-1α in multiple cell lineages. HIF-2α is also frequently overexpressed in solid tumors but its role has been mostly studied in clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer, where HIF-2α has been established as a driver of a more aggressive disease. In this study, the role of SphK1/S1P signaling with regard to HIF-2α was investigated in various cancer cell models including ccRCC cells.

Defects of High-Density Lipoproteins in Coronary Artery Disease Caused by Low Sphingosine-1-Phosphate Content: Correction by Sphingosine-1-Phosphate-Loading.

Background: Sphingosine-1-phosphate (S1P) is a constituent of high-density lipoproteins (HDL) that contributes to their beneficial effects. We have shown decreased HDL-S1P in coronary artery disease (CAD) but its functional relevance remains unclear.

Objectives: This study investigated the functional consequences of reduced HDL-S1P content in CAD and tested if increasing it may improve or restore HDL function.

Activated platelets release sphingosine 1-phosphate and induce hypersensitivity to noxious heat stimuli in vivo.

At the site of injury activated platelets release various mediators, one of which is sphingosine 1-phosphate (S1P). It was the aim of this study to explore whether activated human platelets had a pronociceptive effect in an in vivo mouse model and whether this effect was based on the release of S1P and subsequent activation of neuronal S1P receptors 1 or 3. Human platelets were prepared in different concentrations (10(5)/μl, 10(6)/μl, 10(7)/μl) and assessed in mice with different genetic backgrounds (WT, S1P1 (fl/fl), SNS-S1P1 (-/-), S1P3 (-/-)).

Role of Sphingosine-1-Phosphate in Transplant Vasculopathy Evoked by Anti-HLA Antibody.

Transplant vasculopathy (TV) represents the main cause of late graft failure and limits the long-term success of organ transplantation. Cellular and humoral immune responses contribute to the pathogenesis of the concentric and diffuse intimal hyperplasia of arteries of the grafted organ. We recently reported that the mitogenic signaling, evoked in human vascular smooth muscle cells (hmSMC) by the anti-HLA class I monoclonal antibody W6/32, implicates neutral sphingomyelinase-2, suggesting a role for sphingolipids in intimal hyperplasia of TV.

Neutralizing S1P inhibits intratumoral hypoxia, induces vascular remodelling and sensitizes to chemotherapy in prostate cancer.

Hypoxia promotes neovascularization, increased tumor growth, and therapeutic resistance. The transcription factor, hypoxia-inducible factor 1α (HIF-1α), has been reported as the master driver of adaptation to hypoxia. We previously identified the sphingosine kinase 1/sphingosine 1-phosphate (SphK1/S1P) pathway as a new modulator of HIF-1α under hypoxia.

Anti-S1P Antibody as a Novel Therapeutic Strategy for VEGFR TKI-Resistant Renal Cancer.

Purpose: VEGFR2 tyrosine kinase inhibition (TKI) is a valuable treatment approach for patients with metastatic renal cell carcinoma (RCC). However, resistance to treatment is inevitable. Identification of novel targets could lead to better treatment for patients with TKI-naïve or -resistant RCC.