Search

Polyvinylpyrrolidone (PVP) is a synthetic polymer that holds significance in various fields such as biomedical, medical, and electronics, due to its biocompatibility and exceptional dielectric properties. Electrospinning is the most commonly used tool to fabricate fibers because of its convenience and the wide choice of parameter optimization. Various parameters, including solution molarity, flow rate, voltage, needle gauge, and needle-to-collector distance, can be optimized to obtain the desired morphology of the fibers. Although PVP is commercially available in various molecular weights, PVP with a molecular weight of 130,000 g/mol is generally considered to be the easiest PVP to fabricate fibers with minimal challenges. However, the fiber diameter in this case is usually in the micron regime, which limits the utilization of PVP fibers in fields that require fiber diameters in the nano regime. Generally, PVP with a lower molecular weight, such as 10,000 g/mol and 55,000 g/mol, is known to present challenges in fiber preparation. In the current study, parameter optimization for PVP possessing molecular weights of 10,000 g/mol and 55,000 g/mol was carried out to obtain nanofibers. The electrospinning technique was utilized for fiber fabrication by optimizing the above-mentioned parameters. SEM analysis was performed to analyze the fiber morphology, and quantitative analysis was performed to correlate the effect of parameters on the fiber morphology. This research study will lead to various applications, such as drug encapsulation for sustained drug release and nanoparticles/nanotubes encapsulation for microwave absorption applications. [ABSTRACT FROM AUTHOR]

Innovation in biomedical science is always a field of interest for researchers. Drug delivery, being one of the key areas of biomedical science, has gained considerable significance. The utilization of simple yet effective techniques such as electrospinning has undergone significant development in the field of drug delivery. Various polymers such as PEG (polyethylene glycol), PLGA (Poly(lactic-co-glycolic acid)), PLA(Polylactic acid), and PCA (poly(methacrylate citric acid)) have been utilized to prepare electrospinning-based drug delivery systems (DDSs). Polyvinyl alcohol (PVA) has recently gained attention because of its biocompatibility, biodegradability, non-toxicity, and ideal mechanical properties as these are the key factors in developing DDSs. Moreover, it has shown promising results in developing DDSs individually and when combined with natural and synthetic polymers such as chitosan and polycaprolactone (PCL). Considering the outstanding properties of PVA, the aim of this review paper was therefore to summarize these recent advances by highlighting the potential of electrospun PVA for drug delivery systems. [ABSTRACT FROM AUTHOR]

Microtubule actin crosslinking factor 1 (MACF1), is a cytoskeletal protein that functions as a crosslinker between microtubules and actin filaments, with early studies expanding the role of this spectraplakin protein to the central nervous system and Wnt signaling. In the early 2000's, genetic alterations of MACF1 were identified in several cancers suggesting that this cytoskeletal crosslinker was involved in tumor development and progression, while preclinical studies provided evidence that MACF1 is a potential diagnostic and prognostic biomarker and therapeutic target in glioblastomas, a central nervous system cancer derived from astrocytes and neural progenitor stem cells. Furthermore, investigations in glioblastomas demonstrated that genetic inhibitory targeting of this spectraplakin protein alone and in combination with DNA damaging agents had synergistic antitumorigenic effects. The established role of MACF1 in Wnt signaling, a known mechanistic driver of central nervous system development and pro-tumorigenic cell behavior in glioblastomas, provide a premise for addressing the potential of this spectraplakin protein as a novel oncoprotein in cancers with origins in the nervous system. The present review provides a summary of the role and function of MACF1 in the central nervous system, Wnt signaling and cancer development, specifically as an oncoprotein that underlie the transformation and oncogenic properties of glioblastomas. [ABSTRACT FROM AUTHOR]

The Xenopusinner ear, like that of other vertebrates, is a complex structure comprised of several sensory organs innervated by the VIIIth cranial nerve. Located within each organ is a sensory epithelium containing mechanosensory receptor hair cells arranged in a single layer surrounded by supporting cells. Our laboratory is investigating hair cell differentiation in the various organs during inner ear morphogenesis (Diaz et al, 1995, Hear. Res. 91:33-42; Lopez Anaya et al., 1997, J. Morph. 234:263-276; Quick and Serrano, 1999, Neurosci. Abstr 25:297.9). For this study we used light and confocal laser scanning microscopes (CLSM) to image the organs and hair cells of the inner ear during larval development. Fixed tissue was sectioned for light microscopy and stained with toluidine blue or hematoxylin/eosin. Sectioned tissue and whole mounts were prepared for the CLSM using Alexa 568 phalloidin to detect actin and an Alexa 488 conjugated secondary antibody to label anti-cytokeratin antibody. A BioRad MRC-1024 CLSM was used to collect digitized images of the fluorescent-labeled tissue and the BioRad LaserSharp software was used to render tridimensional images of the inner ear from the digitized data. Results show that stereociliary bundles could be distinguished on presumptive hair cells using the fluorescent phalloidin label, while supporting cells showed a characteristic more intense labeling for cytokeratin than hair cells. The dual-labeling pattern could be used to identify regions of sensory epithelia containing hair cells and their surrounding supporting cells. Results show the gradual development of the compartments of the inner ear from an otic vesicle (Stage 28/30), through the invagination of the primordial sensory epithelium (Stages 42/45), to the formation of distinct auditory and vestibular organs by Stage 56. Supported by NIH and NASA awards to EES and a NASA New Mexico Space Grant Consortium Fellowship to QAQ.

Plakins are a family of seven cytoskeletal cross-linker proteins (microtubule-actin crosslinking factor 1 (MACF), bullous pemphigoid antigen (BPAG1) desmoplakin, envoplakin, periplakin, plectin, epiplakin) that network the three major filaments that comprise the cytoskeleton. Plakins have been found to be involved in disorders and diseases of the skin, heart, nervous system, and cancer that are attributed to autoimmune responses and genetic alterations of these macromolecules. Despite their role and involvement across a spectrum of several diseases, there are no current drugs or pharmacological agents that specifically target the members of this protein family. On the contrary, microtubules have traditionally been targeted by microtubule inhibiting agents, used for the treatment of diseases such as cancer, in spite of the deleterious toxicities associated with their clinical utility. The Research Collaboratory for Structural Bioinformatics (RCSB) was used here to identify therapeutic drugs targeting the plakin proteins, particularly the spectraplakins MACF1 and BPAG1, which contain microtubule-binding domains. RCSB analysis revealed that plakin proteins had 329 ligands, of which more than 50% were MACF1 and BPAG1 ligands and 10 were documented, clinically or experimentally, to have several therapeutic applications as anticancer, anti-inflammatory, and antibiotic agents. [ABSTRACT FROM AUTHOR]

Tyrosine kinase inhibitors are a clinically standard treatment option for non-small cell lung cancers (NSCLCs), the leading cause of cancer-related deaths in the US. These targeted agents include first, second and third generation tyrosine kinase inhibitors; however, these lack clinical efficacy in the treatment of NSCLC due to intrinsic and acquired resistance. This resistance may be a result of genetic aberrations in oncogenic signaling mediators of divergent pathways. The present study aimed to investigate a novel dual tyrosine kinase and PI3K inhibitor, PP121, as a targeted agent in NSCLC cell lines. The present study co-cultured PP121 with healthy human astrocytes, a prevalent cell type located in the brain of NSCLC brain metastases. To date, few preclinical studies have examined the efficacy of PP121 as an anticancer agent, and to the best of my knowledge, no previous studies have previously evaluated its therapeutic potential in the treatment of NSCLC. To investigate the clinical heterogeneity of NSCLC, patient-derived adenocarcinoma (ADC) and squamous cell carcinoma (SCC) xenograft models were used, which exhibited epidermal growth factor receptor (EGFR) mutations and mesenchymal-epithelial transition (MET) factor amplifications. Notably, both EGFR and MET are known contributors to tyrosine kinase inhibitor resistance; thus, the aforementioned mutations and amplifications enabled the effects of PP121 to be evaluated in these solid tumors. In addition, a co-cultured model system using both NSCLC cells and astrocytes was employed to assess the effects of PP121 on the invasion of ADC and SCC cells in a multicellular environment. Results of the present study demonstrated that PP121 exerted an antitumorigenic effect in the aforementioned model systems via downregulation of pharmacodynamic targets. [ABSTRACT FROM AUTHOR]

When I first embarked on a career as an African American biomedical scientist, I felt a personal obligation and responsibility to conduct science with and market science to other African [...]

Background: Fusarochromanone (FC101) is a small molecule fungal metabolite with a host of interesting biological functions, including very potent anti-angiogenic and direct anti-cancer activity. Results: Herein, we report that FC101 exhibits very potent in-vitro growth inhibitory effects (IC50 ranging from 10nM-2.5 μM) against HaCat (pre-malignant skin), P9-WT (malignant skin), MCF-7 (low malignant breast), MDA-231 (malignant breast), SV-HUC (premalignant bladder), UM-UC14 (malignant bladder), and PC3 (malignant prostate) in a time-course and dose-dependent manner, with the UM-UC14 cells being the most sensitive. FC101 induces apoptosis and an increase in proportion of cells in the sub-G1 phase in both HaCat and P9-WT cell lines as evidenced by cell cycle profile analysis. In a mouse xenograft SCC tumor model, FC101 was well tolerated, non-toxic, and achieved a 30% reduction in tumor size at a dose of 8 mg/kg/day. FC101 is also a potent anti-angiogenenic agent. At nanomolar doses, FC101 inhibits the vascular endothelial growth factor-A (VEGF-A)-mediated proliferation of endothelial cells. Conclusions: Our data presented here indicates that FC101 is an excellent lead candidate for a small molecule anti-cancer agent that simultaneously affects angiogenesis signaling, cancer signal transduction, and apoptosis. Further understanding of the underlying FC101's molecular mechanism may lead to the design of novel targeted and selective therapeutics, both of which are pursued targets in cancer drug discovery. [ABSTRACT FROM AUTHOR]

The auditory and vestibular endorgans of the inner ear which are essential for the senses of hearing and balance form early during development when the otocyst undergoes a period of rapid growth and compartmentalization. Here we show the spatial and temporal patterns of proliferating cells in the Xenopus laevis inner ear as this organ develops from an otic vesicle at stage 31 until stage 47, an age at which compartmentalization and the initial appearance of sensory structures are evident. Sites of new cell production were identified in specimens at stages 31, 37, 42, 45 and 47 using immunohistochemical methods to detect bromodeoxyuridine (BrdU) incorporation three hours after exposure to this thymidine analogue. Cells undergoing terminal mitosis at stages 37, 42 and 45 were detected by exposing specimens at these stages to BrdU and permitting development to proceed until stage 47. Our results show that while newly replicating cells are uniformly distributed throughout the stage 31 otic vesicle, they are spatially restricted in stages 37 through 45, with few dividing cells visible in the central patches of the emerging sensory epithelia. In contrast, no clear proliferative pattern was discerned at stage 47. BrdU-positive cells that had undergone terminal mitosis at stage 37, 42 and 45 were detected in the central regions of nascent sensory epithelia at stage 47. These findings are consistent with a developmental mechanism in which cells undergoing terminal mitosis during early X. laevis stages contribute to sensory epithelia and in which cell mixing and migration are features of inner ear compartmentalization. [ABSTRACT FROM AUTHOR]

Microtubule actin crosslinking factor 1 (MACF1), is a cytoskeletal protein that functions as a crosslinker between microtubules and actin filaments, with early studies expanding the role of this spectraplakin protein to the central nervous system and Wnt signaling. In the early 2000's, genetic alterations of MACF1 were identified in several cancers suggesting that this cytoskeletal crosslinker was involved in tumor development and progression, while preclinical studies provided evidence that MACF1 is a potential diagnostic and prognostic biomarker and therapeutic target in glioblastomas, a central nervous system cancer derived from astrocytes and neural progenitor stem cells. Furthermore, investigations in glioblastomas demonstrated that genetic inhibitory targeting of this spectraplakin protein alone and in combination with DNA damaging agents had synergistic antitumorigenic effects. The established role of MACF1 in Wnt signaling, a known mechanistic driver of central nervous system development and pro-tumorigenic cell behavior in glioblastomas, provide a premise for addressing the potential of this spectraplakin protein as a novel oncoprotein in cancers with origins in the nervous system. The present review provides a summary of the role and function of MACF1 in the central nervous system, Wnt signaling and cancer development, specifically as an oncoprotein that underlie the transformation and oncogenic properties of glioblastomas., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2024 Bonner and Quick.)

Background: Microtubule actin crosslinking factor 1 (MACF1) is a spectraplakin cytoskeletal crosslinking protein whose function and role in cancer biology has lacked investigation. Recent studies have identified MACF1 as a novel target in glioblastomas expressed in tissue from tumor patient explants but not normal brain tissue and when silenced has an antitumorigenic impact on these tumors. Radiation as a single agent therapy to treat glioblastomas has been used for decades and has done little to improve survival of individuals diagnosed with this disease. However, contemporary clinical radiotherapy protocols have provided evidence that combinatorial radiotherapy approaches confer a therapeutic benefit in glioblastoma patients. In this study MACF1 was investigated as a radiosensitization target in glioblastomas., Methods: To provide context of MACF1 in glioblastomas, The Cancer Genome Atlas expression analyses were performed in conjunction with genes associated with glioblastoma evolution, while a genetic inhibitory approach, cell migratory assays, and immunofluorescence procedures were used to evaluate responses to MACF1 suppression with radiation. Additionally, expression analyses were conducted to assess co-expression of mTOR signaling pathway regulators and MACF1 in glioblastoma patient samples., Results: Our amalgamation approach demonstrated that negative regulation of MACF1, which was positively correlated with epidermal growth factor receptor and p70s6k expression, enhanced the sensitivity of glioblastoma cells to radiation as a consequence of reducing glioblastoma cell viability and migration. Mechanistically, the antitumorigenic effects on glioblastoma cell behaviors after radiation and impairing MACF1 function were associated with decreased expression of ribosomal protein S6, a downstream effector of p70s6k., Conclusion: MACF1 represents a diagnostic marker with target specificity in glioblastomas that can enhance the efficacy of radiation while minimizing normal tissue toxicity. This approach could potentially expand combinatorial radiation strategies for glioblastoma treatments via impairment of translational regulatory processes that contribute to poor patient survival., Competing Interests: The authors have no potential conflicts of interest., (Copyright © 2020 The Korean Brain Tumor Society, The Korean Society for Neuro-Oncology, and The Korean Society for Pediatric Neuro-Oncology.)

The brain consumes ∼20% of the oxygen utilized in the human body, meaning that brain tumors are vulnerable to paradoxical physiological effects from free radical generation. In the present study, 1'-acetoxychavicol acetate (ACA), a naturally derived antioxidant that inhibits xanthine oxidase, was evaluated for its role as an anti-tumorigenic agent in glioblastomas. The study revealed that ACA inhibited glioblastoma cell proliferation as a consequence of promoting apoptotic cell death by enhancing caspase 3 activity. It was also shown that ACA impaired the migratory ability of glioblastoma cells by decreasing their adhesive properties. Additionally, ACA increased the protein expression levels of the pro-survival signaling cytokines, IL-6 and IL-1α, established cell protectors and survival molecules in brain tumors. Together, these results demonstrate that, despite enhanced expression of compensatory signaling molecules that contribute to tumor cell survival, ACA is an effective pro-apoptotic inducing agent in glioblastomas.

The unfolded protein endoplasmic reticulum stress response has emerged as a cellular physiological target to invoke tumor cell killing due to its homeostatic and cytoprotective functions. In this study, thapsigargin and tunicamycin, two endoplasmic reticulum stress inducers, were investigated for their efficacy on glioblastomas. We demonstrate that clinically relevant concentrations of thapsigargin and tunicamycin eliminate the glioblastoma cell reproductive capacity as a consequence of cell death. The mode of glioblastoma-induced cell death was determined to be via apoptosis as supported by increased C/EBP homologous protein (CHOP) levels and caspase 3 activity, two proteins with established roles in endoplasmic reticulum stress-induced cell death. In conclusion, this study provides evidence that glioblastomas are responsive to endoplasmic reticulum stress induction as a cellular program to eradicate this tumor via programmed cell death.

Invasion of normal brain tissue by brain tumor cells is a major contributing factor to the recurrence and resistance of clinically diagnosed glioblastomas to therapy (surgery, chemotherapy, radiation). Here, we have assessed the efficacy of the microtubule inhibiting agent epothilone B on glioblastoma cell motility, a prerequisite cellular program of invasive glioblastomas. Using cell migration assays and immunofluorescence techniques we demonstrated that epothilone B abrogated glioblastoma cell motility as a consequence of α-actinin 4 redistristrubiton and the breakdown of cellular structures (leading edge, stress fibers) it is associated with during cell migration. Evaluation of the microtubule actin cross linking factor in glioblastoma cells also revealed epothilone B invoked changes in this cytoskeleton cross linking protein, resembling α-actinin 4 changes in response to epothilone B. We have demonstrated in this study that epothilone B antagonizes glioblastoma cell motility due to the disruption of cytoskeleton binding proteins that aide in preserving the structural organization of the cytoskeleton filamentous network. Furthermore, we provide preclincial evidence that epothilone B effects on glioblastomas are not limited to the impairment of dividing tumors cells but that it also targets migratory and invasive glioblastoma cells, suggesting that this agent has potential clinical benefit due to its ability to target divergent cellular programs in the glioblastoma tumor mass.

Glioblastomas are intrinsically resistant to conventional radiation therapy. The present study investigated the possibility that the tyrosine kinase inhibitor, imatinib, could enhance radiation sensitivity and influence proliferative recovery after irradiation in glioblastoma cells. Radiosensitivity was evaluated by clonogenic survival; apoptotic cell death was evaluated using flow cytometric analysis; proliferative recovery was monitored based on viable cell number subsequent to radiation-induced growth arrest; activation of p44/42 MAPK was based on phosphorylation of the protein. Glioblastoma cells pretreated with imatinib demonstrated an enhanced sensitivity to radiation. Imatinib also delayed proliferative recovery in irradiated glioblastoma cells. Imatinib promoted suppression of p44/42 MAPK signaling both when added prior to and post-irradiation. Increased sensitivity to radiation and delayed proliferative recovery in irradiated glioblastoma cells exposed to imatinib may be a consequence of the capacity of imatinib to interfere with p44/42 MAPK kinase signaling. Imatinib may prove to have clinical utility as a neoadjuvant and adjuvant in the treatment of glioblastomas that receive radiation therapy.

Object: Radiotherapy is one of the few treatment options available for glioblastoma multiforme (GBM); however, the basis for its overall ineffectiveness in GBM is not fully understood. The present study was designed to explore the nature of the response to ionizing radiation in GBM cells to gain insight into the basis for the general failure of radiotherapy in the treatment of this disease., Methods: The response to fractionated radiotherapy was examined in GBM cell lines with differing p53 status. A viable cell number was determined during an 8-day period; accelerated senescence was based on beta-galactosidase staining and cell morphology; apoptosis was evaluated by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling assay and fluorescence-activated cell-sorter analysis, whereas the expression of cell-cycle regulatory proteins was monitored by Western blot analysis. Based on clonogenic survival, the wild-type p53 U87 cells and mutant p53 T98 cells demonstrated essentially identical sensitivity to fractionated radiotherapy; however, neither cell line underwent apoptosis, and the primary response to irradiation was growth arrest. The wild-type p53 GBM cells showed clear evidence of accelerated senescence in response to irradiation. In contrast, senescence was not evident in mutant p53 GBM cells or GBM cells in which p53 function was abrogated by the viral E6 protein. The T98 (mutant p53) cells demonstrated a relatively robust proliferative recovery whereas both the rate and extent of recovery were attenuated in the wild-type p53 U87 cells., Conclusions: Both accelerated senescence and conventional growth arrest are likely to represent alternative responses to apoptosis in irradiated GBM cells.

The formation of the eight independent endorgan compartments (sacculus, utricle, horizontal canal, anterior canal, posterior canal, lagena, amphibian papilla, and basilar papilla) of the Xenopus laevis inner ear is illustrated as the otic vesicle develops into a complex labyrinthine structure. The morphology of transverse sections and whole-mounts of the inner ear was assessed in seven developmental stages (28, 31, 37, 42, 45, 47, 50) using brightfield and laser scanning confocal microscopy. The presence of mechanosensory hair cells in the sensory epithelia was determined by identification of stereociliary bundles in cryosectioned tissue and whole-mounts of the inner ear labeled with the fluorescent F-actin probe Alexa-488 phalloidin. Between stages 28 and 45, the otic vesicle grows in size, stereociliary bundles appear and increase in number, and the pars inferior and pars superior become visible. The initial formation of vestibular compartments with their nascent stereociliary bundles is seen by larval stage 47, and all eight vestibular and auditory compartments with their characteristic sensory fields are present by larval stage 50. Thus, in Xenopus, inner ear compartments are established between stages 45 and 50, a 2-week period during which the ear quadruples in length in the anteroposterior dimension. The anatomical images presented here demonstrate the morphological changes that occur as the otic vesicle forms the auditory and vestibular endorgans of the inner ear. These images provide a resource for investigations of gene expression patterns in Xenopus during inner ear compartmentalization and morphogenesis., (Developmental Dynamics 234:791-801, 2005. (c) 2005 Wiley-Liss, Inc.)