Simultaneous, Real-Time Detection of Glutamate and Dopamine in Rat Striatum Using Fast-Scan Cyclic Voltammetry.

Glutamate and dopamine (DA) represent two key contributors to striatal functioning, a region of the brain that is essential to motor coordination and motivated behavior. While electroanalytical techniques can be utilized for rapid, spatially resolved detection of DA in the interferent-rich brain environment, glutamate, a nonelectroactive analyte, cannot be directly detected using electroanalytical techniques. However, it can be probed using enzyme-based sensors, which generate an electroactive reporter in the presence of glutamate. The vast majority of glutamate biosensors have relied on amperometric sensing, which is an inherently nonselective detection technique. This approach necessitates the use of complex and performance-limiting modifications to ensure the desired single-analyte specificity. Here, we present a novel glutamate microbiosensor fabricated on a carbon-fiber microelectrode substrate and coupled with fast-scan cyclic voltammetry (FSCV) to enable the simultaneous quantification of glutamate and DA at single recording sites in the brain, which is impossible when using typical amperometric approaches. The glutamate microbiosensors were characterized for sensitivity, stability, and selectivity by using a voltammetric waveform optimized for the simultaneous detection of both species. The applicability of these sensors for the investigation of neural circuits was validated in the rat ventral striatum. Electrically evoked glutamate and DA release were recorded at single-micrometer-scale locations before and after pharmacological manipulation of glutamatergic signaling. Our novel glutamate microbiosensor advances the state of the art by providing a powerful tool for probing coordination between these two species in a way that has previously not been possible.

BCL9/STAT3 regulation of transcriptional enhancer networks promote DCIS progression.

The molecular processes by which some human ductal carcinoma in situ (DCIS) lesions advance to the more aggressive form, while others remain indolent, are largely unknown. Experiments utilizing a patient-derived (PDX) DCIS Mouse INtraDuctal (MIND) animal model combined with ChIP-exo and RNA sequencing revealed that the formation of protein complexes between B Cell Lymphoma-9 (BCL9), phosphoserine 727 STAT3 (PS-727-STAT3) and non-STAT3 transcription factors on chromatin enhancers lead to subsequent transcription of key drivers of DCIS malignancy. Downregulation of two such targets, integrin ß3 and its associated metalloproteinase, MMP16, resulted in a significant inhibition of DCIS invasive progression. Finally, in vivo targeting of BCL9, using rosemary extract, resulted in significant inhibition of DCIS malignancy in both cell line and PDX DCIS MIND animal models. As such, our studies provide compelling evidence for future testing of rosemary extract as a chemopreventive agent in breast cancer.

Insights on the Molecular Characteristics of Molecularly Imprinted Polymers as Monitored by Sum Frequency Generation Spectroscopy.

Sensing in molecularly imprinted polymers (MIPs) requires specific interactions of the imprinted polymer and the approaching template molecule. These interactions are affected by the morphology of the polymer surface, the affinity of the template molecule to the polymer network, and the steric approach. In this particular study, a template molecule, metronidazole, is studied with respect to the typically used methacrylic acid-based imprinted polymer using a combination of bulk and surface techniques. The resulting infrared (IR) spectra exhibited the presence of the template molecule in the polymer matrix as well as their efficient removal after washing. Dipping of the MIP according to what is expected of facile sensing in an aqueous solution of metronidazole did not show any presence of the template molecule in the bulk of the MIP, as observed by IR spectroscopy. However, using sum frequency generation (SFG) spectroscopy, the CH aromatic stretch of the imidazole ring positioned at ∼3100 cm-1 was observed at the polymer surface, including its inner pores or cavities, and at the buried polymer-fused silica interface after dipping. SFG studies have also shown the vibrational signatures of the polymer matrix, the presence of the template molecule on the surface, and the detection of residual template molecules after washing. Increasing the washing time to 50 min has proven to be less effective than increasing the washing cycles to three. However, after the third cycle, reorganization of the polymer matrix was evident as also the complete removal of the template molecule. The observed changes from the acquired images using scanning electron microscopy and atomic force microscopy show the structural morphologies of MIPs and a good distribution of the pores across the MIP surface. The study demonstrates the importance of combining both bulk and surface characterization in providing insight into the template molecule-polymer network interactions.

Cardiotoxicity of cancer therapeutics: current issues in screening, prevention, and therapy.

In the context of modern cancer chemotherapeutics, cancer survivors are living longer and being exposed to potential comorbidities related to non-cancer side effects of such treatments. With close monitoring of cancer patients receiving potentially cardiotoxic medical therapies, oncologists, and cardiologists alike are identifying patients in both clinical and subclinical phases of cardiovascular disease related to such chemotherapies. Specifically, cardiotoxicity at the level of the myocardium and potential for the development of heart failure are becoming a growing concern with increasing survival of cancer patients. Traditional chemotherapeutic agents used commonly in the treatment of breast cancer and hematologic malignancies, such as anthracyclines and HER-2 antagonists, are well known to be associated with cardiovascular sequelae. Patients often present without symptoms and an abnormal cardiac imaging study performed as part of routine evaluation of patients receiving cardiotoxic therapies. Additionally, patients can present with signs and symptoms of cardiovascular disease months to years after receiving the chemotherapies. As the understanding of the physiology underlying the various cancers has grown, therapies have been developed that target specific molecules that represent key aspects of physiologic pathways responsible for cancer growth. Inhibition of these pathways, such as those involving tyrosine kinases, has lead to the potential for cardiotoxicity as well. In view of the potential cardiotoxicity of specific chemotherapies, there is a growing interest in identifying patients who are at risk of cardiotoxicity prior to becoming symptomatic or developing cardiotoxicity that may limit the use of potentially life-saving chemotherapy agents. Serological markers and novel cardiac imaging techniques have become the source of many investigations with the goal of screening patients for pre-clinical cardiotoxicity. Additionally, studies have been performed.