Tumor Treating Fields (TTFields) Concomitant with Immune Checkpoint Inhibitors Are Therapeutically Effective in Non-Small Cell Lung Cancer (NSCLC) In Vivo Model.

Tumor Treating Fields (TTFields) are electric fields that exert physical forces to disrupt cellular processes critical for cancer cell viability and tumor progression. TTFields induce anti-mitotic effects through the disruption of the mitotic spindle and abnormal chromosome segregation, which trigger several forms of cell death, including immunogenic cell death (ICD). The efficacy of TTFields concomitant with anti-programmed death-1 (anti-PD-1) treatment was previously shown in vivo and is currently under clinical investigation.

Pulsed-Focused Ultrasound Slows B16 Melanoma and 4T1 Breast Tumor Growth through Differential Tumor Microenvironmental Changes.

Focused ultrasound (FUS) has shown promise as a non-invasive treatment modality for solid malignancies. FUS targeting to tumors has been shown to initiate pro-inflammatory immune responses within the tumor microenvironment. Pulsed FUS (pFUS) can alter the expression of cytokines, chemokines, trophic factors, cell adhesion molecules, and immune cell phenotypes within tissues.

Hyaluronan control of the primary vascular barrier during early mouse pregnancy is mediated by uterine NK cells.

Successful implantation is associated with a unique spatial pattern of vascular remodeling, characterized by profound peripheral neovascularization surrounding a periembryo avascular niche. We hypothesized that hyaluronan controls the formation of this distinctive vascular pattern encompassing the embryo. This hypothesis was evaluated by genetic modification of hyaluronan metabolism, specifically targeted to embryonic trophoblast cells.

Acoustic Radiation or Cavitation Forces From Therapeutic Ultrasound Generate Prostaglandins and Increase Mesenchymal Stromal Cell Homing to Murine Muscle.

Non-ablative ultrasound (US)-based techniques to improve targeted tropism of systemically infused cell therapies, particularly mesenchymal stromal cell (MSC), have gained attention in recent years. Mechanotransduction following targeted US sonications have been shown to modulate tissue microenvironments by upregulating cytokines, chemokines, and trophic factors in addition to vascular cell adhesion molecules (CAM) that are necessary to promote tropism of MSC. While numerous US treatment parameters have demonstrated increased MSC homing, it remains unclear how the different mechanical US forces [i.

The Impact of Focused Ultrasound in Two Tumor Models: Temporal Alterations in the Natural History on Tumor Microenvironment and Immune Cell Response.

Image-guided focused ultrasound (FUS) has been successfully employed as an ablative treatment for solid malignancies by exposing immune cells to tumor debris/antigens, consequently inducing an immune response within the tumor microenvironment (TME). To date, immunomodulation effects of non-ablative pulsed-FUS (pFUS) on the TME are poorly understood. In this study, the temporal differences of cytokines, chemokines, and trophic factors (CCTFs) and immune cell populations induced by pFUS were interrogated in murine B16 melanoma or 4T1 breast cancer cells subcutaneously inoculated into C57BL/6 or BALB/c mice.

The Proteomic Effects of Pulsed Focused Ultrasound on Tumor Microenvironments of Murine Melanoma and Breast Cancer Models.

Non-ablative pulsed focused ultrasound (pFUS) targets non-thermal forces that activate local molecular and cellular immune responses. Optimal parameters to stimulate immunotherapeutic tumor microenvironments (TME) and responses in different tumor types remain uninvestigated. Flank B16 murine melanoma and 4T1 breast tumors received 1 MHz pFUS at 1-8 MPa peak negative pressures (PNP) and were analyzed 24 hr post-sonication.

Tuftelin Is Required for NGF-Induced Differentiation of PC12 Cells.

Nerve growth factor (NGF) promotes pleiotropic gene transcription-dependent biological effects, in neuronal and non-neuronal cells, including survival, proliferation, differentiation, neuroprotection, pain, and angiogenesis. It is hypothesized that during odontogenesis, NGF may be implicated in morphogenetic and mineralization events by affecting proliferation and/or differentiation of dental cells. Tuftelin belongs to the enamel associated teeth proteins and is thought to play a role in enamel mineralization.

Chlorotoxin-A Multimodal Imaging Platform for Targeting Glioma Tumors.

Chlorotoxin (CTX) is a 36-amino-acid disulfide-containing peptide derived from the venom of the scorpion . CTX alters physiology in numerous ways. It interacts with voltage gated chloride channels, Annexin-2, and matrix metalloproteinase-2 (MMP-2).

Reverting the molecular fingerprint of tumor dormancy as a therapeutic strategy for glioblastoma.

Glioblastoma is an aggressive and invasive brain malignancy with high mortality rates despite current treatment modalities. In this study, we show that a 7-gene signature, previously found to govern the switch of glioblastomas from dormancy to aggressive tumor growth, correlates with improved overall survival of patients with glioblastoma. Using glioblastoma dormancy models, we validated the role of 2 genes from the signature, thrombospondin-1 ( TSP-1) and epidermal growth factor receptor ( EGFR), as regulators of glioblastoma dormancy and explored their therapeutic potential.

Protein toxins of the Echis coloratus viper venom directly activate TRPV1.

Background: Peptide and protein toxins are essential tools to dissect and probe the biology of their target receptors. Venoms target vital physiological processes to evoke pain. Snake venoms contain various factors with the ability to evoke, enhance and sustain pain sensation.

Enhanced therapeutic anti-inflammatory effect of betamethasone on topical administration with low-frequency, low-intensity (20 kHz, 100 mW/cm(2)) ultrasound exposure on carrageenan-induced arthritis in a mouse model.

The purpose of this work was to investigate whether low-frequency, low-intensity (20 kHz, <100 mW/cm(2), spatial-peak, temporal-peak intensity) ultrasound, delivered with a lightweight (<100 g), tether-free, fully wearable, battery-powered applicator, is capable of reducing inflammation in a mouse model of rheumatoid arthritis. The therapeutic, acute, anti-inflammatory effect was estimated from the relative swelling induced in mice hindlimb paws. In an independent, indirect approach, the inflammation was bio-imaged by measuring glycolytic activity with near-infrared labeled 2-deoxyglucose.

Transcriptional down-regulation of epidermal growth factor (EGF) receptors by nerve growth factor (NGF) in PC12 cells.

Nerve growth factor (NGF) treatment causes a profound down-regulation of epidermal growth factor (EGF) receptors (EGFR) during the neuronal differentiation of PC12 cells. This process was characterized by a progressive decrease in EGFR level, as measured by (125)I-EGF binding and Scatchard analysis, tyrosine phosphorylation, Western blotting, and bio-imaging using EGF-labeled with a near-infrared probe. Differentiation of the cells with NGF for 5-7 days produces a 95 % reduction in the amount of (35)S-methionine-labeled EGFR.

Vimocin and vidapin, cyclic KTS peptides, are dual antagonists of α1β1/α2β1 integrins with antiangiogenic activity.

Obtustatin and viperistatin, members of the disintegrin protein family, served as lead compounds for the synthesis of linear and cyclic peptides containing the KTS binding motif. The most active linear peptide, a viperistatin analog, indicated the importance of Cys(19) and Cys(29), as well as the presence of Arg at position 24 for their biologic activity, and was used as the basic sequence for the synthesis of cyclic peptides. Vimocin (compound 6) and vidapin (compound 10) showed a high potency (IC50 = 0.

Neurotherapeutic effect of cord blood derived CD45+ hematopoietic cells in mice after traumatic brain injury.

Treatment of traumatic brain injury (TBI) is still an unmet need. Cell therapy by human umbilical cord blood (HUCB) has shown promising results in animal models of TBI and is under evaluation in clinical trials. HUCB contains different cell populations but to date, only mesenchymal stem cells have been evaluated for therapy of TBI.

Cytocompatibility of novel extracellular matrix protein analogs of biodegradable polyester polymers derived from α-hydroxy amino acids.

One of the challenges in regenerative medicine is the development of novel biodegradable materials to build scaffolds that will support multiple cell types for tissue engineering. Here we describe the preparation, characterization, and cytocompatibility of homo- and hetero-polyesters of α-hydroxy amino acid derivatives with or without lactic acid conjugation. The polymers were prepared by a direct condensation method and characterized using gel permeation chromatography, (1)H-nuclear magnetic resonance spectroscopy, Fourier transform infrared spectroscopy, differential scanning calorimetry, optical activity, and solubility.

The effects of a chactoid scorpion venom and its purified toxins on rat blood pressure and mast cells histamine release.

The effect of the venom of the Chactoid family of scorpions on blood pressure was scantly investigated and was addressed in the present study using the venom of the Israeli scorpion, Scorpio maurus palmatus. Blood pressure in rats was monitored via cannulated femoral artery, while venom and toxins were introduced into femoral vein. Venom injection elicited a biphasic effect, expressed first by a fast and transient hypotensive response, which lasted up to 10 min, followed by a hypertensive response, which lasted up to one hour.

Near infrared optical visualization of epidermal growth factor receptors levels in COLO205 colorectal cell line, orthotopic tumor in mice and human biopsies.

In this study, we present the applicability of imaging epidermal growth factor (EGF) receptor levels in preclinical models of COLO205 carcinoma cells in vitro, mice with orthotopic tumors and ex vivo colorectal tumor biopsies, using EGF-labeled with IRDye800CW (EGF-NIR). The near infrared (NIR) bio-imaging of COLO205 cultures indicated specific and selective binding, reflecting EGF receptors levels. In vivo imaging of tumors in mice showed that the highest signal/background ratio between tumor and adjacent tissue was achieved 48 hours post-injection.

Vixapatin (VP12), a c-type lectin-protein from Vipera xantina palestinae venom: characterization as a novel anti-angiogenic compound.

A C-type lectin-like protein (CTL), originally identified as VP12 and lately named Vixapatin, was isolated and characterized from Israeli viper Vipera xantina palestinae snake venom. This CTL was characterized as a selective α2β1 integrin inhibitor with anti-melanoma metastatic activity. The major aim of the present study was to prove the possibility that this protein is also a potent novel anti-angiogenic compound.

Bio-imaging of colorectal cancer models using near infrared labeled epidermal growth factor.

Novel strategies that target the epidermal growth factor receptor (EGFR) have led to the clinical development of monoclonal antibodies, which treat metastatic colorectal cancer (mCRC) but only subgroups of patients with increased wild type KRAS and EGFR gene copy, respond to these agents. Furthermore, resistance to EGFR blockade inevitably occurred, making future therapy difficult. Novel bio-imaging (BOI) methods may assist in quantization of EGFR in mCRC tissue thus complementing the immunohistochemistry methodology, in guiding the future treatment of these patients.

Nerve growth factor stimulation of ERK1/2 phosphorylation requires both p75NTR and α9β1 integrin and confers myoprotection towards ischemia in C2C12 skeletal muscle cell model.

The functions of nerve growth factor (NGF) in skeletal muscles physiology and pathology are not clear and call for an updated investigation. To achieve this goal we sought to investigate NGF-induced ERK1/2 phosphorylation and its role in the C2C12 skeletal muscle myoblasts and myotubes. RT-PCR and western blotting experiments demonstrated expression of p75(NTR), α9β1 integrin, and its regulator ADAM12, but not trkA in the cells, as also found in gastrocnemius and quadriceps mice muscles.

Angioneural crosstalk in scaffolds with oriented microchannels for regenerative spinal cord injury repair.

The aim of our work is to utilize the crosstalk between the vascular and the neuronal system to enhance directed neuritogenesis in uniaxial guidance scaffolds for the repair of spinal cord injury. In this study, we describe a method for angioneural regenerative engineering, i.e.

Multimodal neuroprotection induced by PACAP38 in oxygen-glucose deprivation and middle cerebral artery occlusion stroke models.

Pituitary adenylate cyclase activating peptide (PACAP), a potent neuropeptide which crosses the blood-brain barrier, is known to provide neuroprotection in rat stroke models of middle cerebral artery occlusion (MCAO) by mechanism(s) which deserve clarification. We confirmed that following i.v.