Designing Multivalent and Multispecific Biologics.

In the era of precision medicine, multivalent and multispecific therapeutics present a promising approach for targeted disease intervention. These therapeutics are designed to interact with multiple targets simultaneously, promising enhanced efficacy, reduced side effects, and resilience against drug resistance. We dissect the principles guiding the design of multivalent biologics, highlighting challenges and strategies that must be considered to maximize therapeutic effect.

Facile Display of Homomultivalent Proteins for Selections.

Low-affinity protein binders are emerging as valuable domains for therapeutic applications because of their higher specificity when presented in multivalent ligands that increase the overall strength and selectivity of receptor binding. discovery of low-affinity binders would be enhanced by the large library sizes attainable with selection systems, but these platforms generally maximize recovery of high-affinity monovalent binders. Here, we present a facile technology that uses rolling circle amplification to create homomultivalent libraries.

Engineering a Minimal Leucine-rich Repeat IgG-binding Module.

Sea lamprey immunization can yield leucine-rich repeat (LRR) protein binders analogous to globular antibodies developed from mammals. A novel minimal LRR was discovered through lamprey immunization with human immunoglobulin G Fc domain (IgG Fc). Initial attempts to solubly express this LRR protein, VLRB.

Plectin is a novel regulator for apical extrusion of RasV12-transformed cells.

Several lines of evidence have revealed that newly emerging transformed cells are often eliminated from the epithelium, though the underlying molecular mechanisms of this cancer preventive phenomenon still remain elusive. In this study, using mammalian cell culture systems we have identified plectin, a versatile cytoskeletal linker protein, as a novel regulator for apical extrusion of RasV12-transformed cells. Plectin is accumulated in RasV12 cells when they are surrounded by normal epithelial cells.

Nano-Cesium for Anti-Cancer Properties: An Investigation into Cesium Induced Metabolic Interference.

The use of cesium chloride (CsCl) for cancer therapy ("high pH therapy") has been theorized to produce anticancer properties by raising intracellular pH to induce apoptosis. Although considered as "alternative medicine", little scientific evidence supports this theory. Alternatively, cells have no cesium ion (Cs) mediated channels for clearance.

Vibrational spectroscopy and imaging for concurrent cellular trafficking of co-localized doxorubicin and deuterated phospholipid vesicles.

Simultaneous tracking of nanoparticles and encapsulated payload is of great importance and visualizing their activity is arduous. Here we use vibrational spectroscopy to study the in vitro tracking of co-localized lipid nanoparticles and encapsulated drug employing a model system derived from doxorubicin-encapsulated deuterated phospholipid (dodecyl phosphocholine-d38) single tailed phospholipid vesicles.

Regulating Biocompatibility of Carbon Spheres via Defined Nanoscale Chemistry and a Careful Selection of Surface Functionalities.

A plethora of nanoarchitectures have been evaluated preclincially for applications in early detection and treatment of diseases at molecular and cellular levels resulted in limited success of their clinical translation. It is important to identify the factors that directly or indirectly affect their use in human. We bring a fundamental understanding of how to adjust the biocompatibility of carbon based spherical nanoparticles (CNPs) through defined chemistry and a vigilant choice of surface functionalities.

Combinatorial therapy for triple negative breast cancer using hyperstar polymer-based nanoparticles.

We report the ability of a novel combinatorial therapy obtained from nanoparticles of hyperstar polymers encompassing drugs to selectively target triple negative breast cancer (TNBC) cell proliferation through STAT3 and topoisomerase-II pathways. This nano-cocktail was at least two to four fold better than the individual drugs and 6-20 times more selective than the parent drugs.

EPLIN is a crucial regulator for extrusion of RasV12-transformed cells.

At the initial stage of carcinogenesis, a mutation occurs in a single cell within a normal epithelial layer. We have previously shown that RasV12-transformed cells are apically extruded from the epithelium when surrounded by normal cells. However, the molecular mechanisms underlying this phenomenon remain elusive.

Next generation carbon nanoparticles for efficient gene therapy.

In a pursuit to develop a commercially exploitable and traceable gene delivery vehicle, here, we develop next generation carbon nanoparticle-DNA complex (CNPLex). CNPLexes were used to transfect green fluorescent protein (GFP) reporter gene containing plasmid DNA (pDNA) pEGFP-N1 targeting breast cancer cells MCF-7 and MDA-MB231. Prepared CNPs were optimized for particle size, surface potential, polymer surface decoration, absorbance efficiency, fluorescence efficiency, IR spectroscopic signatures, and DNA loading and release efficiencies.

Filamin acts as a key regulator in epithelial defence against transformed cells.

Recent studies have shown that certain types of transformed cells are extruded from an epithelial monolayer. However, it is not known whether and how neighbouring normal cells play an active role in this process. In this study, we demonstrate that filamin A and vimentin accumulate in normal cells specifically at the interface with Src- or RasV12-transformed cells.

PKA-regulated VASP phosphorylation promotes extrusion of transformed cells from the epithelium.

At the early stages of carcinogenesis, transformation occurs in single cells within tissues. In an epithelial monolayer, such mutated cells are recognized by their normal neighbors and are often apically extruded. The apical extrusion requires cytoskeletal reorganization and changes in cell shape, but the molecular switches involved in the regulation of these processes are poorly understood.

Alg14 organizes the formation of a multiglycosyltransferase complex involved in initiation of lipid-linked oligosaccharide biosynthesis.

Protein N-glycosylation begins with the assembly of a lipid-linked oligosaccharide (LLO) on the endoplasmic reticulum (ER) membrane. The first two steps of LLO biosynthesis are catalyzed by a functional multienzyme complex comprised of the Alg7 GlcNAc phosphotransferase and the heterodimeric Alg13/Alg14 UDP-GlcNAc transferase on the cytosolic face of the ER. In the Alg13/14 glycosyltransferase, Alg14 recruits cytosolic Alg13 to the ER membrane through interaction between their C-termini.

A canine case of skull base meningioma treated with hydroxyurea.

An 11-year-old female miniature schnauzer was tentatively diagnosed with the skull base meningioma, based on several examinations. Because surgical treatment was difficult, and outpatient radiation therapy was not available in the local area, chemotherapy with hydroxyurea combined with dexamethasone was selected. The patient's clinical symptoms improved after one week of treatment, and the tumor size was obviously reduced on MRI performed 37 days after treatment began.

Multiple metastases of thyroid cancer in the cranium and pituitary gland in two dogs.

Two dogs, a 14-year-old, female American Eskimo dog and a 14-year-old, male Maltese dog, were presented with thalamic syndromes, including lowered levels of consciousness, poor postural responses and presence of masses in the neck region. In both dogs, magnetic resonance imaging revealed multiple masses inside the cranium, including the pituitary gland. One dog died from status epilepticus two days after magnetic resonance imaging and the other died two months after magnetic resonance imaging from respiratory failure.

Four strains of spontaneously hyperlipidemic (SHL) mice: phenotypic distinctions determined by genetic backgrounds.

Spontaneously hyperlipidemic (SHL) mice are Japanese wild mice (KOR) with disruption of the apolipoprotein E (Apo E) gene. These mice (KOR-Apoe(shl)) are superhypercholesterolemic and develop severe xanthoma, but their atherosclerosis is relatively mild compared with Apo E knockout mice. First, we tested whether this distinction is due to additional mutation of the Apoc1 and/or Apoc2 genes in KOR-Apoe(shl).