Cancer remains a major cause of morbidity and mortality around the world. Improved cancer treatment requires enhancing cancer diagnosis and detection. To achieve this goal, here we reported a novel imaging probe, pH-responsive fluorescent graphene quantum dots (pRF-GQDs). pRF-GQDs were prepared by electrolysis of graphite rods in sodium p-toluenesulfonate acetonitrile solution. The resulting pRF-GQDs, which have minimal toxicity, display a sharp fluorescence transition between green and blue at pH 6.8, a pH matching the acidic extracellular microenvironment in solid tumors. We found that this unique fluorescence switch property allows distinguishing tumors from normal tissues. In addition to fluorescence, pRF-GQDs also bear the upconversion photoluminescence (UCPL) property. We demonstrate that the combination of UCPL and fluorescence switch enables detecting solid tumors of different origin at an early developmental stage. Therefore, pRF-GQDs have great potential to be used as a universal probe for fluorescence-guided cancer surgery and cancer diagnosis.

Glioblastoma (GBM) is the most common primary brain cancer in adults where tumor cell heterogeneity and sex differences influence clinical outcomes. Here, we functionally characterize three male and three female patient-derived GBM cell lines, identify protumorigenic BTICs, and create novel male and female preclinical models of GBM. Cell lines were evaluated on the following features: proliferation, stemness, migration, tumorigenesis, clinical characteristics, and sensitivity to radiation, TMZ, rhTNFSF10 (rhTRAIL), and rhBMP4. All cell lines were classified as GBM according to epigenetic subtyping, were heterogenous and functionally distinct from one another, and re-capitulated features of the original patient tumor. In establishing male and female preclinical models, it was found that two male-derived GBM cell lines (QNS108 and QNS120) and one female-derived GBM cell line (QNS315) grew at a faster rate in female mice brains. One male-derived GBM cell line (QNS108) decreased survival in female mice in comparison with male mice. However, no survival differences were observed for mice injected with a female-derived cell line (QNS315). In summary, a panel of six GBM patient-derived cell lines were functionally characterized, and it was shown that BTIC lines can be used to construct sex-specific models with differential phenotypes for additional studies.

Glioblastoma (GBM) is the most devastating brain cancer, and cures remain elusive with currently available neurosurgical, pharmacological, and radiation approaches. While retrovirus- and adenovirus-mediated suicide gene therapy using DNA encoding herpes simplex virus-thymidine kinase (HSV-tk) and prodrug ganciclovir has been suggested as a promising strategy, a nonviral approach for treatment in an orthotopic human primary brain tumor model has not previously been demonstrated. Delivery challenges include nanoparticle penetration through brain tumors, efficient cancer cell uptake, endosomal escape to the cytosol, and biodegradability. To meet these challenges, we synthesized poly­(ethylene glycol)–modified poly­(beta-amino ester) (PEG–PBAE) polymers to improve extracellular delivery and coencapsulated plasmid DNA with end-modified poly­(beta-amino ester) (ePBAE) polymers to improve intracellular delivery as well. We created and evaluated a library of PEG–PBAE/ePBAE nanoparticles (NPs) for effective gene therapy against two independent primary human stem-like brain tumor initiating cells, a putative target to prevent GBM recurrence. The optimally engineered PEG–PBAE/ePBAE NP formulation demonstrated 54 and 82% transfection efficacies in GBM1A and BTIC375 cells respectively, in comparison to 37 and 66% for optimized PBAE NPs without PEG. The leading PEG–PBAE NP formulation also maintained sub-250 nm particle size up to 5 h, while PBAE NPs without PEG showed aggregation over time to micrometer-sized complexes. The comparative advantage demonstrated in vitro successfully translated into improved in vivo diffusion, with a higher amount of PEG–PBAE NPs penetrating to a distance of 2 mm from the injection site. A significant increase in median survival from 53.5 to 67 days by PEG–PBAE/pHSV-tk NP and systemic ganciclovir treatment compared to a control group in orthotopic murine model of human glioblastoma demonstrates the potential of PEG–PBAE-based NPs as an effective gene therapy platform for the treatment of human brain tumors.

MPJ extension has a profound effect on increasing forefoot plantar soft tissue stiffness and a consistent but minimal effect on reducing soft tissue thickness. These changes may help transform the foot into a rigid lever at push-off consistent with the theory of the windlass mechanism.