Superlative and Selective Sensing of Serotonin in Undiluted Human Serum Using Novel Polystyrene Sulfonate Conductive Polymer.

In the past 5 years, real-time health monitoring has become ubiquitous with the development of watches and rings that can measure and report on the physiological state. As an extension, real-time biomarker sensors, such as the continuous glucose monitor, are becoming popular for both health and performance monitoring. However, few real-time sensors for biomarkers have been made commercially available; this is primarily due to problems with cost, stability, sensitivity, selectivity, and reproducibility of biosensors. Therefore, simple, robust sensors are needed to expand the number of analytes that can be detected in emerging and existing wearable platforms. To address this need, we present a simple but novel sensing material. In short, we have modified the already popular PEDOT/PSS conductive polymer by completely removing the PEDOT component and thus have fabricated a polystyrene sulfonate (PSS) sensor electrodeposited on a glassy carbon (GC) base (GC-PSS). We demonstrate that coupling the GC-PSS sensor with differential pulse voltammetry creates a sensor capable of the selective and sensitive detection of serotonin. Notably, the GC-PSS sensor has a sensitivity of 179 µA µM-1 cm-2 which is 36x that of unmodified GC and an interferent-free detection limit of 10 nM, which is below the concentrations typically found in saliva, urine, and plasma. Notably, the redox potential of serotonin interfacing with the GC-PSS sensor is at -0.188 V versus Ag/AgCl, which is significantly distanced from peaks produced by common interferants found in biofluids, including serum. Therefore, this paper reports a novel, simple sensor and polymeric interface that is compatible with emerging wearable sensor platforms.

Electrochemical biosensor for rapid detection of fungal contamination in fuel systems.

There is an increased demand for real-time monitoring of biological and biochemical processes. While most sensor research focuses on physiological conditions, less has been done towards developing real-time biosensors that can operate in and survive exposure to extreme environments and harsh chemicals such as fuel. One interesting application is monitoring microbial load in fuel tanks to prevent both fuel spoilage and biocorrosion. We developed a comprehensive method to enable the first reagentless, real-time, microbial sensor platform that is also fuel resistant. We first identified an extracellular protein epitope conserved in fuel-degrading fungi then used this epitope to develop a suitable biorecognition element (BRE) through biopanning of a 7-mer phage displayed peptide library. After demonstrating the BRE's affinity to fungi using molecular and fluorescence assays, we incorporated the BRE into a reagentless, real-time electrochemical sensing platform based on a self-assembled monolayer of peptide BREs and redox reporters. Finally, we incorporated this real-time electrochemical sensing platform into a microfluidic device. We demonstrated detection of Yarrowia lipolytica as low as 1 × 104 CFU/mL in a bath cell, and demonstrate a microfluidic cell that functions even after exposure to jet fuel. In summary, this work describes development of a fuel-resistant biosensor for monitoring microbial growth in extreme environments.

Imaging Modality and Frequency in Surveillance of Stage I Seminoma Testicular Cancer: Results From a Randomized, Phase III, Noninferiority Trial (TRISST).

PURPOSE: Survival in stage I seminoma is almost 100%. Computed tomography (CT) surveillance is an international standard of care, avoiding adjuvant therapy. In this young population, minimizing irradiation is vital. The Trial of Imaging and Surveillance in Seminoma Testis (TRISST) assessed whether magnetic resonance images (MRIs) or a reduced scan schedule could be used without an unacceptable increase in advanced relapses. METHODS: A phase III, noninferiority, factorial trial. Eligible participants had undergone orchiectomy for stage I seminoma with no adjuvant therapy planned. Random assignment was to seven CTs (6, 12, 18, 24, 36, 48, and 60 months); seven MRIs (same schedule); three CTs (6, 18, and 36 months); or three MRIs. The primary outcome was 6-year incidence of Royal Marsden Hospital stage ≥ IIC relapse (> 5 cm), aiming to exclude increases ≥ 5.7% (from 5.7% to 11.4%) with MRI (v CT) or three scans (v 7); target N = 660, all contributing to both comparisons. Secondary outcomes include relapse ≥ 3 cm, disease-free survival, and overall survival. Intention-to-treat and per-protocol analyses were performed. RESULTS: Six hundred sixty-nine patients enrolled (35 UK centers, 2008-2014); mean tumor size was 2.9 cm, and 358 (54%) were low risk (< 4 cm, no rete testis invasion). With a median follow-up of 72 months, 82 (12%) relapsed. Stage ≥ IIC relapse was rare (10 events). Although statistically noninferior, more events occurred with three scans (nine, 2.8%) versus seven scans (one, 0.3%): 2.5% absolute increase, 90% CI (1.0 to 4.1). Only 4/9 could have potentially been detected earlier with seven scans. Noninferiority of MRI versus CT was also shown; fewer events occurred with MRI (two [0.6%] v eight [2.6%]), 1.9% decrease (-3.5 to -0.3). Per-protocol analyses confirmed noninferiority. Five-year survival was 99%, with no tumor-related deaths. CONCLUSION: Surveillance is a safe management approach-advanced relapse is rare, salvage treatment successful, and outcomes excellent, regardless of imaging frequency or modality. MRI can be recommended to reduce irradiation; and no adverse impact on long-term outcomes was seen with a reduced schedule.

Pevonedistat (MLN4924): mechanism of cell death induction and therapeutic potential in colorectal cancer.

Pevonedistat (MLN4924), a selective inhibitor of the NEDD8-activating enzyme E1 regulatory subunit (NAE1), has demonstrated significant therapeutic potential in several malignancies. Although multiple mechanisms-of-action have been identified, how MLN4924 induces cell death and its potential as a combinatorial agent with standard-of-care (SoC) chemotherapy in colorectal cancer (CRC) remains largely undefined. In an effort to understand MLN4924-induced cell death in CRC, we identified p53 as an important mediator of the apoptotic response to MLN4924. We also identified roles for the extrinsic (TRAIL-R2/caspase-8) and intrinsic (BAX/BAK) apoptotic pathways in mediating the apoptotic effects of MLN4924 in CRC cells, as well as a role for BID, which modulates a cross-talk between these pathways. Depletion of the anti-apoptotic protein FLIP, which we identify as a novel mediator of resistance to MLN4924, enhanced apoptosis in a p53-, TRAIL-R2/DR5-, and caspase-8-dependent manner. Notably, TRAIL-R2 was involved in potentiating the apoptotic response to MLN4924 in the absence of FLIP, in a ligand-independent manner. Moreoever, when paired with SoC chemotherapies, MLN4924 demonstrated synergy with the irinotecan metabolite SN38. The cell death induced by MLN4924/SN38 combination was dependent on activation of mitochondria through BAX/BAK, but in a p53-independent manner, an important observation given the high frequency of TP53 mutation(s) in advanced CRC. These results uncover mechanisms of cell death induced by MLN4924 and suggest that this second-generation proteostasis-disrupting agent may have its most widespread activity in CRC, in combination with irinotecan-containing treatment regimens.

Co3O4 needles on Au honeycomb as a non-invasive electrochemical biosensor for glucose in saliva.

While glucose monitoring technology is widely available, the continued prevalence of diabetes around the world coupled with its debilitating effects continues to grow. The significant limitations which exist in the current technology, instils the need for materials capable of non-invasive glucose detection. In this study a unique non-enzymatic electrochemical glucose sensor was developed, utilising a gold honeycomb-like framework upon which sharp Co3O4 needles are anchored. This composite nanomaterial demonstrates excellent sensing performance in glucose concentrations ranging between 20 µM and 4 mM, exceeding the range required for non-invasive glucose sensing. In conjunction with this high sensitivity (2.014 mA mM-1·cm-2), the material possesses excellent selectivity towards glucose for commonly interfering physiological species such as uric acid and ascorbic acid. Glucose detection in synthetic saliva was then performed showing excellent capability in the low concentration range (20 µM-1 mM) for non-invasive sensing performance. Further tests showed good selectivity of the sensor in physiological contaminants commonly found in saliva such as cortisol and dopamine. This development provides excellent scope to create next-generation non-invasive diabetes monitoring platforms, with excellent performance when detecting low glucose concentrations in complex solutions such as saliva.

Multi-directional electrodeposited gold nanospikes for antibacterial surface applications.

The incorporation of high-aspect-ratio nanostructures across surfaces has been widely reported to impart antibacterial characteristics to a substratum. This occurs because the presence of such nanostructures can induce the mechanical rupture of attaching bacteria, causing cell death. As such, the development of high-efficacy antibacterial nano-architectures fabricated on a variety of biologically relevant materials is critical to the wider acceptance of this technology. In this study, we report the antibacterial behavior of a series of substrata containing multi-directional electrodeposited gold (Au) nanospikes, as both a function of deposition time and precursor concentration. Firstly, the bactericidal efficacy of substrata containing Au nanospikes was assessed as a function of deposition time to elucidate the nanopattern that exhibited the greatest degree of biocidal activity. Here, it was established that multi-directional nanospikes with an average height of ∼302 nm ± 57 nm (formed after a deposition time of 540 s) exhibited the greatest level of biocidal activity, with ∼88% ± 8% of the bacterial cells being inactivated. The deposition time was then kept constant, while the concentration of the HAuCl4 and Pb(CH3COO)2 precursor materials (used for the formation of the Au nanospikes) was varied, resulting in differing nanospike architectures. Altering the Pb(CH3COO)2 precursor concentration produced multi-directional nanostructures with a wider distribution of heights, which increased the average antibacterial efficacy against both Gram-negative Pseudomonas aeruginosa and Gram-positive Staphylococcus aureus bacteria. Importantly, the in situ electrochemical fabrication method used in this work is robust and straightforward, and is able to produce highly reproducible antibacterial surfaces. The results of this research will assist in the wider utilization of mechano-responsive nano-architectures for antimicrobial surface technologies.

Nanowire Morphology of Mono- and Bidoped α-MnO2 Catalysts for Remarkable Enhancement in Soot Oxidation.

In the present work, nanowire morphologies of α-MnO2, cobalt monodoped α-MnO2, Cu and Co bidoped α-MnO2, and Ni and Co bidoped α-MnO2 samples were prepared by a facile hydrothermal synthesis. The structural, morphological, surface, and redox properties of all the as-prepared samples were investigated by various characterization techniques, namely, scanning electron microscopy (SEM), transmission and high resolution electron microscopy (TEM and HR-TEM), powder X-ray diffraction (XRD), N2 sorption surface area measurements, X-ray photoelectron spectroscopy (XPS), hydrogen-temperature-programmed reduction (H2-TPR), and oxygen-temperature-programmed desorption (O2-TPD). The soot oxidation performance was found to be significantly improved via metal mono- and bidoping. In particular, Cu and Co bidoped α-MnO2 nanowires showed a remarkable improvement in soot oxidation performance, with its T50 (50% soot conversion) values of 279 and 431 °C under tight and loose contact conditions, respectively. The soot combustion activation energy for the Cu and Co bidoped MnO2 nanowires is 121 kJ/mol. The increased oxygen vacancies, greater number of active sites, facile redox behavior, and strong synergistic interaction were the key factors for the excellent catalytic activity. The longevity of Cu and Co bidoped α-MnO2 nanowires was analyzed, and it was found that the Cu/Co bidoped α-MnO2 nanowires were highly stable after five successive cycles and showed an insignificant decrease in soot oxidation activity. Furthermore, the HR-TEM analysis of a spent catalyst after five cycles indicated that the (310) crystal plane of α-MnO2 interacts with the soot particles; therefore, we can assume that more-reactive exposed surfaces positively affect the reaction of soot oxidation. Thus, the Cu and Co bidoped α-MnO2 nanowires provide promise as a highly effective alternative to precious metal based automotive catalysts.

Co3O4@CeO2 hybrid flower-like microspheres: a strong synergistic peroxidase-mimicking artificial enzyme with high sensitivity for glucose detection.

In recent years, the development of artificial nanostructured enzymes has received enormous interest in nanobiotechnology due to their advantages over natural enzymes. In the present work, different amounts (5, 10, and 20 wt%) of Co3O4 nanoparticle decorated CeO2 hybrid flower-like microspheres (Co3O4@CeO2) have been investigated for peroxidase-like activity and it was found that 10 wt% of Co3O4@CeO2 exhibited excellent peroxidase-like activity for the catalytic oxidation of the 3,3',5,5'-tetramethylbenzidine (TMB) substrate in the presence of H2O2. The formation of more Ce3+ ions associated with the oxygen vacancies and a strong synergistic interaction between CeO2 and Co3O4 may be responsible for the enhanced peroxidase-like activity. Based on their peroxidase activity, Co3O4@CeO2 hybrid microspheres were used for the colourimetric detection of glucose. It was found that Co3O4@CeO2 hybrid microspheres showed a substantial enhancement in the detection selectivity. The limit of detection (LOD) was also improved with a limit as low as 1.9 µM. Thus, we believe that Co3O4@CeO2 hybrid flower-like microspheres with high peroxidase-like activity can be exploited for biosensing applications.

Nickel-gold bimetallic monolayer colloidal crystals fabricated via galvanic replacement as a highly sensitive electrochemical sensor.

Bimetallic Ni-Au monolayer colloidal crystals (MCCs) were fabricated by galvanic replacement of Ni monolayers with Au salt. The influence of Au concentration used in the galvanic replacement solutions on the morphology and structure of the resulting Ni-Au surface is studied. It was found that the use of monolayer colloidal crystals, which display cohesive structure formations across the monolayer, results in the galvanic replacement reaction occurring more evenly over the surface when compared to the thin film counterpart. The fabricated devices were analyzed under alkaline conditions using chronoamperometric techniques to detect glucose concentrations ranging between 20 µM and 10 mM. The optimum Ni-Au MCC substrate was produced using 0.1 mM Au salt solution and showed a very low experimental detection limit of 14.9 µM and a calculated sensitivity of 506 µA mM-1 cm-2, which was ∼3 times larger than that of the plain Ni MCC substrate. The Ni-Au MCC substrate also showed minimal current response changes in the presence of common physiological contaminants, thus being a highly selective electrochemical glucose sensor.

Fe-doped CeO2 nanorods for enhanced peroxidase-like activity and their application towards glucose detection.

The construction of highly efficient inorganic mimetic enzymes (nanozymes) is much needed to replace natural enzymes due to their instability and high cost. Recently, nanoscale CeO2 has been attracting significant interest due to its unique properties such as facile redox behaviour (Ce4+↔ Ce3+) and surface defects. In the present work, various amounts of Fe3+-doped CeO2 nanorods (NRs) (with 3, 6, 9, and 12% Fe doping) were synthesized using a facile hydrothermal method and investigated for peroxidase-like activity and glucose detection. The peroxidase-like activity results revealed that 6 at% doping is the optimal Fe doping level to demonstrate superior catalytic performance over un-doped and Fe3+-doped CeO2 NRs. Steady state kinetic analysis also confirms that the 6% Fe3+-doped CeO2 (6Fe/CeO2) NRs exhibited excellent catalytic performance towards 3,3',5,5'tetramethylbenzidine (TMB) oxidation with a Km and Vm of 0.176 mM and 8.6 × 10-8 M s-1, respectively, as compared to horseradish peroxidase (HRP) enzymes (0.434 mM and 10.0 × 10-8 M s-1). Typical colour reactions arising from the catalytic oxidation of the TMB substrate over 6Fe/CeO2 NRs with H2O2 have been utilized to establish a simple sensitive and selective colorimetric assay for the determination of glucose concentration in buffer, diluted fruit juices and foetal bovine serum samples. The superior catalytic performance of 6Fe/CeO2 NRs could be attributed to abundant surface defects, high surface area and pore volume, and preferential exposure of the highly reactive (110) planes.

A Nanoengineered Conductometric Device for Accurate Analysis of Elemental Mercury Vapor.

We developed a novel conductometric device with nanostructured gold (Au) sensitive layer which showed high-performance for elemental mercury (Hg(0)) vapor detection under simulated conditions that resemble harsh industrial environments. That is, the Hg(0) vapor sensing performance of the developed sensor was investigated under different operating temperatures (30-130 °C) and working conditions (i.e., humid) as well as in the presence of various interfering gas species, including ammonia (NH3), hydrogen sulfide (H2S), nitric oxide (NO), carbon mono-oxide (CO), carbon dioxide (CO2), sulfur dioxide (SO2), hydrogen (H2), methane (CH4), and volatile organic compounds (VOCs) such as ethylmercaptan (EM), acetaldehyde (MeCHO) and methyl ethyl ketone (MEK) among others. The results indicate that the introduction of Au nanostructures (referred to as nanospikes) on the sensor's surface enhanced the sensitivity toward Hg(0) vapor by up-to 450%. The newly developed sensor exhibited a limit of detection (LoD) (∼35 µg/m(3)), repeatability (∼94%), desorption efficiency (100%) and selectivity (∼93%) when exposed to different concentrations of Hg(0) vapor (0.5 to 9.1 mg/m(3)) and interfering gas species at a chosen operating temperature of 105 °C. Furthermore, the sensor was also found to show 91% average selectivity when exposed toward harsher industrial gases such as NO, CO, CO2, and SO2 along with same concentrations of Hg(0) vapor in similar operating conditions. In fact, this is the first time a conductometric sensor is shown to have high selectivity toward Hg(0) vapor even in the presence of H2S. Overall results indicate that the developed sensor has immense potential to be used as accurate online Hg(0) vapor monitoring technology within industrial processes.

Immune modulation in advanced radiotherapies: Targeting out-of-field effects.

By virtue of being a localized treatment modality, radiotherapy is unable to deliver a tumoricidal radiation dose to tissues outside of the irradiated field. Nevertheless, ionizing radiation may result in radiation damage mediated by a bystander like effect away from the irradiated field, but this response is likely to be modest when radiotherapy is the sole treatment modality. Over the last decade there has been a re-emergence of immune modulating therapies as anti-cancer treatment modalities. Clinical trials on vaccines have on the whole been largely disappointing, but greater response rates have been observed from the immune checkpoint modulators. A clinical benefit of using such agents has been shown in disease sites such as melanoma and non-small cell lung cancer. There is growing pre-clinical data and a number of case reports which suggest the presence of abscopal effects when radiotherapy is co-administered with immune checkpoint inhibitors, suggesting that this combination may lead to an enhanced tumour response outside of the primary treatment field. In this review, the mechanisms of such an enhanced out-of-field tumour response, the potential clinical utilities, the optimal radiotherapy delivery and considerations for clinical follow-up following treatment are discussed.

Achieving optimal dose intensity with adjuvant chemotherapy in elderly breast cancer patients: a 10-year retrospective study in a UK institution.

The study was to determine if breast cancer patients aged 65 and above could be given adjuvant chemotherapy safely while achieving an acceptable relative dose intensity of at least 85%. We identified all patients aged 65 and over who received adjuvant chemotherapy over the 10 year period, November 1999 to October 2009, and determined the proportion that achieved a relative dose intensity of at least 85% as well as the tolerability of their treatment. A total of 101 patients were identified, with a median age of 69 years (range 65-78).Of these, 25.7% of patients had at least one major comorbidity, 84.2% had a tumor size of 5 cm or less, 73.3% were node positive and 58.4% were hormone receptor positive. The chemotherapy regimens used were AC (Doxorubicin and Cyclophosphamide), FEC (Fluorouracil, Epirubicin, and Cyclophosphamide), CMF (Cyclophosphamide, Methotrexate, and Fluorouracil) and ECMF (Epirubicin followed by CMF). Seventy-nine patients (78.2%) achieved the relative dose intensity of at least 85%. With respect to toxicity, 11.9% of patients developed febrile neutropenia and 23.8% of patients required hospital admission during the treatment period, but there were no treatment-related deaths in the group. A significant proportion of patients aged 65 and above achieved the intended dose intensity of at least 85% over this 10-year period, with manageable toxicity levels. This supports the use of these regimens as adjuvant chemotherapy for breast cancer in this age group.

Prognostic significance of TRAIL signaling molecules in stage II and III colorectal cancer.

PURPOSE: We previously found that cellular FLICE-inhibitory protein (c-FLIP), caspase 8, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor 2 (DR5) are major regulators of cell viability and chemotherapy-induced apoptosis in colorectal cancer. In this study, we determined the prognostic significance of c-FLIP, caspase 8, TRAIL and DR5 expression in tissues from patients with stage II and III colorectal cancer. EXPERIMENTAL DESIGN: Tissue microarrays were constructed from matched normal and tumor tissue derived from patients (n = 253) enrolled in a phase III trial of adjuvant 5-fluorouracil-based chemotherapy versus postoperative observation alone. TRAIL, DR5, caspase 8, and c-FLIP expression levels were determined by immunohistochemistry. RESULTS: Colorectal tumors displayed significantly higher expression levels of c-FLIP (P < 0.001), caspase 8 (P = 0.01), and DR5 (P < 0.001), but lower levels of TRAIL (P < 0.001) compared with matched normal tissue. In univariate analysis, higher TRAIL expression in the tumor was associated with worse overall survival (P = 0.026), with a trend to decreased relapse-free survival (RFS; P = 0.06), and higher tumor c-FLIP expression was associated with a significantly decreased RFS (P = 0.015). Using multivariate predictive modeling for RFS in all patients and including all biomarkers, age, treatment, and stage, we found that the model was significant when the mean tumor c-FLIP expression score and disease stage were included (P < 0.001). As regards overall survival, the overall model was predictive when both TRAIL expression and disease stage were included (P < 0.001). CONCLUSIONS: High c-FLIP and TRAIL expression may be independent adverse prognostic markers in stage II and III colorectal cancer and might identify patients most at risk of relapse.