Enzymes underpin physiological function and exhibit dysregulation in many disease-associated microenvironments and aberrant cell processes. Exploiting altered enzyme activity and expression for ...diagnostics, drug targeting, and drug release is tremendously promising. When combined with booming research in nanobiotechnology, enzyme-responsive nanomaterials used for controlled drug release have achieved significant development and have been studied as an important class of drug delivery strategies in nanomedicine. In this review, we describe enzymes such as proteases, phospholipases and oxidoreductases that serve as delivery triggers. Subsequently, we explore recently developed enzyme-responsive nanomaterials with versatile applications for extracellular and intracellular drug delivery. We conclude by discussing future opportunities and challenges in this area.
Purpose: Tissue-mimicking phantoms (TMPs) are synthetic materials designed to replicate properties of biological tissues. There is a need to quantify temperature changes following ultrasound or ...magnetic resonance imaging-guided high intensity focused ultrasound (MR-HIFU). This work describes development, characterization and evaluation of tissue-mimicking thermochromic phantom (TMTCP) for direct visualization and quantification of HIFU heating. The objectives were to (1) develop an MR-imageable, HIFU-compatible TMTCP that reports absolute temperatures, (2) characterize TMTCP physical properties and (3) examine TMTCP color change after HIFU.
Methods and materials: A TMTCP was prepared to contain thermochromic ink, silicon dioxide and bovine serum albumin (BSA) and its properties were quantified. A clinical MRI-guided and a preclinical US-guided HIFU system were used to perform sonications in TMTCP. MRI thermometry was performed during HIFU, followed by T2-weighted MRI post-HIFU. Locations of color and signal intensity change were compared to the sonication plan and to MRI temperature maps.
Results: TMTCP properties were comparable to those in human soft tissues. Upon heating, the TMTCP exhibited an incremental but permanent color change for temperatures between 45 and 70 °C. For HIFU sonications the TMTCP revealed spatially sharp regions of color change at the target locations, correlating with MRI thermometry and hypointense regions on T2-weighted MRI. TMTCP-based assessment of various HIFU applications was also demonstrated.
Conclusions: We developed a novel MR-imageable and HIFU-compatible TMTCP to characterize HIFU heating without MRI or thermocouples. The HIFU-optimized TMTCP reports absolute temperatures and ablation zone geometry with high spatial resolution. Consequently, the TMTCP can be used to evaluate HIFU heating and may provide an in vitro tool for peak temperature assessment, and reduce preclinical in vivo requirements for clinical translation.
Igf2 mRNA binding protein 1 (IMP1, CRD-BP, ZBP-1) is a messenger RNA binding protein that we have shown previously to regulate colorectal cancer (CRC) cell growth in vitro. Furthermore, increased ...IMP1 expression correlates with enhanced metastasis and poor prognosis in CRC patients. In the current study, we sought to elucidate IMP1-mediated functions in CRC pathogenesis in vivo. Using CRC cell xenografts, we demonstrate that IMP1 overexpression promotes xenograft tumor growth and dissemination into the blood. Furthermore, intestine-specific knockdown of Imp1 dramatically reduces tumor number in the Apc (Min/+) mouse model of intestinal tumorigenesis. In addition, IMP1 knockdown xenografts exhibit a reduced number of tumor cells entering the circulation, suggesting that IMP1 may directly modulate this early metastatic event. We further demonstrate that IMP1 overexpression decreases E-cadherin expression, promotes survival of single tumor cell-derived colonospheres and promotes enrichment and maintenance of a population of CD24+CD44+ cells, signifying that IMP1 overexpressing cells display evidence of loss of epithelial identity and enhancement of a tumor-initiating cell phenotype. Taken together, these findings implicate IMP1 as a modulator of tumor growth and provide evidence for a novel role of IMP1 in early events in CRC metastasis.
Tumour and tumour microenvironment exploitation of immunologic checkpoints like PDL1 can enable immune evasion. Recent advances in oncology, have brought forward antibody drugs, such as anti-PD-L1, ...capable of blocking and/or mediating the eradication of cells that express PD-L1. Despite promise across a wide range of indications, clinically such agents meaningfully extend survival only in a fraction of patients treated. Immature, heterogenous blood vessels, elevated interstitial pressures, and stromal barriers severely limit the accumulation and extravasation of drugs within the tumour microenvironment. We hypothesize that the physical size of antibody therapeutics, such as antiPD-L1, compounded by delivery barriers could be a factor limiting their efficacy. Recently, submicron cavitation nucleation agents, sonosensitive particles (SSPs), activated by focused ultrasound have been shown to improve the delivery of large, anti-cancer therapeutics via microstreaming-mediated transport. Our aim was to pre-clinically investigate whether systemically-dosed anti-PD-L1 followed by SSPs and the application of focused ultrasound could improve the intratumoural delivery and therapeutic efficacy of anti-PD-L1. Efficacy studies revealed that pairing anti-PD-L1 with ultrasound-mediated cavitation can significantly extend median survival time. Cavitation was also found to enhance the intratumoural accumulation of anti-PD-L1 and three other antibodies. Further, the binding intensity and distribution of anti-PD-L1 improved in cavitation-treated tumours. Immunological analysis suggests that anti-PD-L1 paired with cavitation enables the innate and adaptive immune system to leverage the modest cavitation-induced inflammation and improved anti-PDL1 delivery to facilitate tumour attack. Taken in a broader context, this pre-clinical work suggests that ultrasound-mediated cavitation warrants further investigation as viable tool to improve drug delivery clinically.
Vaccines are arguably the most important medical technology developed to date. However, effective treatment of diseases such as breast cancer have so far evaded standard vaccination strategies. One ...popular target for cancer treatment is the cell surface membrane protein, ErbB-2, also known as Her-2 or neu. It is localised to the cell surface and has raised expression in 15–30% of all breast cancers, as well as in ovarian, colon and lung cancer. Here, a liposomal system comprised of spatially separated ErbB-2 peptide, to activate B cells, and ovalbumin peptide OVA323−339, to provide non-cognate T cell support, was used to generate antibodies against the epitope of the ErbB-2 protein targeted by Pertuzumab, a monoclonal antibody licensed for the treatment of ErbB-2 expressing cancers. After just 7 days a raised (7.3-fold, p<0.01), isotype-switched, humoral immune response specific for the ErbB-2 peptide was achieved in mice with pre-existing immunity to OVA which were exposed to liposomes with external ErbB-2 and internal OVA323−339. The absence of pre-existing OVA immunity in the mice or OVA323−339 peptide in the liposomes removed the effect. The effect of this anti-ErbB-2 antibody response was characterised against an ErbB-2 overexpressing tumour cell line both in vitro and in vivo. Notably, antibody responses were demonstrated to induce cell death in vitro, resulting in 96% reduction in viable cells. This study, therefore, demonstrates the feasibility of this approach to generate a rapid, high-titre, isotype-switched, antibody response that specifically targets ErbB-2 overexpression on tumour cells and is capable of inducing cell death in vitro in the absence of complement or immune cells.
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Background
Residency programs compete to attract applicants based on numerous factors. Previous research has suggested that medical students consider quality of life among the most important factors ...in selecting a program. One aspect of workplace quality of life is the cadre of non-monetary benefits offered to employees. However, with federal funding for graduate medical education (GME) under consideration for spending cuts, the source and continuation of such benefits may be in question.
Questions/Purposes
This study aimed to determine the level and variability of benefits beyond standard salary and insurance options available to trainees at US orthopedic residency programs and to assess the source of funding for those benefits.
Methods
A 26-question survey investigating various benefits and funding sources was circulated by email to all ACGME-accredited orthopedic residency programs.
Results
The survey was sent to 153 programs and 69 responded (45%). The majority offers their residents discretionary funds (77%) and conference funding (96%), most of which comes from the department, followed by the hospital or GME funding. Forty-one percent of respondents permit their residents to moonlight. The majority of respondents provide meal stipends (93%), free parking (71%), gym benefits (63%), surgical loupes (53%), and maternity/paternity leave beyond vacation time (55%). No statistically significant differences were found among top ranked residencies, top ranked orthopedic hospitals, or academic centers compared to their counterparts.
Conclusion
While some benefits are commonly offered, there is great variation in the availability and level of others. However, these differences were independent of program and hospital reputation as well as academic center status. Departments currently bear a substantial amount of the cost of these benefits internally.
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