Low-Cost, High-Pressure-Synthesized Oxygen-Entrapping Materials to Improve Treatment of Solid Tumors.

Tumor hypoxia drives resistance to many cancer therapies, including radiotherapy and chemotherapy. Methods that increase tumor oxygen pressures, such as hyperbaric oxygen therapy and microbubble infusion, are utilized to improve the responses to current standard-of-care therapies. However, key obstacles remain, in particular delivery of oxygen at the appropriate dose and with optimal pharmacokinetics. Toward overcoming these hurdles, gas-entrapping materials (GeMs) that are capable of tunable oxygen release are formulated. It is shown that injection or implantation of these materials into tumors can mitigate tumor hypoxia by delivering oxygen locally and that these GeMs enhance responsiveness to radiation and chemotherapy in multiple tumor types. This paper also demonstrates, by comparing an oxygen (O2 )-GeM to a sham GeM, that the former generates an antitumorigenic and immunogenic tumor microenvironment in malignant peripheral nerve sheath tumors. Collectively the results indicate that the use of O2 -GeMs is promising as an adjunctive strategy for the treatment of solid tumors.

In vitro inhibition of glutathione-S-transferase by dopamine and its metabolites, 3,4-dihydroxyphenylacetaldehyde and 3,4-dihydroxyphenylacetic acid.

Parkinson's disease is characterized by dopamine dyshomeostasis and oxidative stress. The aldehyde metabolite of dopamine, 3,4-dihydroxyphenylacetaldehyde (DOPAL), has been reported to be cytotoxic and capable of protein modification. Protein modification by DOPAL has been implicated in the pathogenesis of Parkinson's disease, but the complete pathology is unknown. Our findings show that DOPAL modifies glutathione S-transferase (GST), an important enzyme in the antioxidant defense system. DOPAL, dopamine, and the metabolite 3,4-dihydroxyphenylacetic acid (DOPAC), inhibited the activity of GST isolated from N27 dopaminergic cells at an IC50 of 31.46 µM, 82.32 µM, and 260.0 µM, respectively. DOPAL, dopamine, and DOPAC inhibited commercially available equine liver GST at an IC50 of 23.72 µM, 32.17 µM, and 73.70 µM, respectively. This inhibition was time dependent and irreversible. 1 mM ʟ-cysteine or glutathione fully protected GST activity from DOPAL, DA, and DOPAC inhibition. 1 mM carnosine partially protected GST activity from DA inhibition. Furthermore, ʟ-cysteine was found to protect GST by forming a putative thiazolidine conjugate with DOPAL. We conclude that GST inactivation may be a part of the broader etiopathology of Parkinson's disease.

Polymer sequencing by molecular machines: a framework for predicting the resolving power of a sliding contact force spectroscopy sequencing method.

We evaluate an AFM-based single molecule force spectroscopy method for mapping sequences in otherwise difficult to sequence heteropolymers, including glycosylated proteins and glycans. The sliding contact force spectroscopy (SCFS) method exploits a sliding contact made between a nanopore threaded over a polymer axle and an AFM probe. We find that for sliding α- and ß-cyclodextrin nanopores over a wide range of hydrophilic monomers, the free energy of sliding is proportional to the sum of two dimensionless, easily calculable parameters representing the relative partitioning of the monomer inside the nanopore or in the aqueous phase, and the friction arising from sliding the nanopore over the monomer. Using this relationship we calculate sliding energies for nucleic acids, amino acids, glycan and synthetic monomers and predict on the basis of these calculations that SCFS will detect N- and O-glycosylation of proteins and patterns of sidechains in glycans. For these applications, SCFS offers an alternative to sequence mapping by mass spectrometry or newly-emerging nanopore technologies that may be easily implemented using a standard AFM.

Sliding Contact Dynamic Force Spectroscopy Method for Interrogating Slowly Forming Polymer Cross-Links.

Dynamic single-molecule force spectroscopy (SMFS), conducted most commonly using AFM, has become a widespread and valuable tool for understanding the kinetics and thermodynamics of fundamental molecular processes such as ligand-receptor interactions and protein unfolding. Where slowly forming bonds are responsible for the primary characteristics of a material, as is the case in cross-links in some polymer gels, care must be taken to ensure that a fully equilibrated bond has first formed before its rupture can be interpreted. Here we introduce a method, sliding contact force spectroscopy (SCFS), that effectively eliminates the kinetics of bond formation from the measurement of bond rupture. In addition, it permits bond rupture measurements in systems where one of the binding partners may be introduced into solution prior to binding without tethering to a surface. Taking as an example of a slowly forming bond, the "eggbox" junction cross-links between oligoguluronic acid chains (oligoGs) in the commercially important polysaccharide alginate, we show that SCFS accurately measures the equilibrated bond strength of the cross-link when one chain is introduced into the sample solution without tethering to a surface. The results validate the SCFS technique for performing single-molecule force spectroscopy experiments and show that it has advantages in cases where the bond to be studied forms slowly and where tethering of one of the binding partners is impractical.

Single molecule investigation of the onset and minimum size of the calcium-mediated junction zone in alginate.

One of the principal roles of alginate, both natively and in commercial applications, is gelation via Ca(2+)-mediated crosslinks between blocks of guluronic acid. In this work, single molecule measurements were carried out between well-characterised series of nearly monodisperse guluronic acid blocks ('oligoGs') using dynamic force spectroscopy. The measurements provide evidence that for interaction times on the order of tens of milliseconds the maximum crosslink strength is achieved by pairs of oligoGs long enough to allow the coordination of 4Ca(2+) ions, with both shorter and longer oligomers forming weaker links. Extending the interaction time from tens to hundreds of milliseconds allows longer oligoGs to achieve much stronger crosslinks but does not change the strength of individual links between shorter oligoGs. These results are considered in light of extant models for the onset of cooperative crosslinking in polyelectrolytes and an anisotropic distribution of oligoGs on interacting surfaces and provide a timescale for the formation and relaxation of alginate gels at the single crosslink level.

A feasibility study to determine if minimally trained medical students can identify markers of chronic parasitic infection using bedside ultrasound in rural Tanzania.

BACKGROUND: Parasitic infections pose a significant health risk in developing nations and are a major cause of morbidity and mortality worldwide. In the Republic of Tanzania, the CDC estimates that 51.5% of the population is infected with one or more intestinal parasites. If diagnosed early, the consequences of chronic parasitic infection can potentially be avoided. METHODS: Six first-year medical students were recruited to enroll patients in the study. They underwent ten hours of formal, hands-on, ultrasound which included basic cardiac, hepatobiliary, renal, pulmonary and FAST scan ultrasound. A World Health Organization protocol with published grading scales was adapted and used to assess for pathology in each patient's liver, bladder, kidneys, and spleen. RESULTS: A total of 59 patients were enrolled in the study. Students reported a sensitivity of 96% and specificity of 100% for the presence of a dome shaped bladder, a sensitivity and specificity of 100% for bladder thickening, a sensitivity and specificity of 100% for portal hypertension and ascites. The sensitivity was 81% with a specificity of 100% for presence of portal vein distention. The sensitivity was 100% with a specificity of 90% for dilated bowel. CONCLUSIONS: Ultrasound has shown a promise at helping to identify pathology in rural communities with limited resources such as Tanzania. Our data suggest that minimally trained first year medical students are able to perform basic ultrasound scans that can identify ultrasonographic markers of parasitic infections.

A feasibility study to determine if minimally trained medical students can identify markers of chronic parasitic infection using bedside ultrasound in rural Tanzania / 世界急诊医学杂志（英文）

@#BACKGROUND: Parasitic infections pose a significant health risk in developing nations and are a major cause of morbidity and mortality worldwide. In the Republic of Tanzania, the CDC estimates that 51.5％ of the population is infected with one or more intestinal parasites. If diagnosed early, the consequences of chronic parasitic infection can potentially be avoided. METHODS: Six first-year medical students were recruited to enroll patients in the study. They underwent ten hours of formal, hands-on, ultrasound which included basic cardiac, hepatobiliary, renal, pulmonary and FAST scan ultrasound. A World Health Organization protocol with published grading scales was adapted and used to assess for pathology in each patient's liver, bladder, kidneys, and spleen. RESULTS: A total of 59 patients were enrolled in the study. Students reported a sensitivity of 96％ and specificity of 100％ for the presence of a dome shaped bladder, a sensitivity and specificity of 100％ for bladder thickening, a sensitivity and specificity of 100％ for portal hypertension and ascites. The sensitivity was 81％ with a specificity of 100％ for presence of portal vein distention. The sensitivity was 100％ with a specificity of 90％ for dilated bowel. CONCLUSIONS: Ultrasound has shown a promise at helping to identify pathology in rural communities with limited resources such as Tanzania. Our data suggest that minimally trained first year medical students are able to perform basic ultrasound scans that can identify ultrasonographic markers of parasitic infections.