Corrigendum to: Physicochemical insights of irradiation-enhanced hydroxyl radical generation from ZnO nanoparticles.

[This corrects the article DOI: 10.1039/c5tx00384a.].

Label-Free in Situ pH Monitoring in a Single Living Cell Using an Optical Nanoprobe.

Intracellular pH plays critical roles in cell and tissue functions during processes such as metabolism, proliferation, apoptosis, ion transportation, endocytosis, muscle contraction and so on. It is thus an important biomarker that can readily be used to monitor the physiological status of a cell. Thus, disrupted intracellular pH may serve as an early indicator of cell dysfunction and deterioration. Various methods have been developed to detect cellular pH, such as pH-sensitive labeling reagents with fluorescent or Raman signals. However, excessive cellular uptake of these reagents will not only disrupt cell viability but also compromise effective long-term monitoring. Here, we present a novel fiber-optic fluorescent nanoprobe with a high spatial resolution for label-free, subcellular pH sensing. The probe has a fast response time (~20 seconds) with minimum invasiveness and excellent pH resolution (0.02 pH units) within a biologically relevant pH environment ranging from 6.17 to 8.11. Its applicability was demonstrated on cultured A549 lung cancer cells, and its efficacy was further testified in two typical cytotoxic cases using carbonylcyanide 3-chlorophenyl hydrazine, titanium dioxide, and nanoparticles. The probe can readily detect the pH variations among cells under toxin/nanoparticles administration, enabling direct monitoring of the early onset of physiological or pathological events with high spatiotemporal resolution. This platform has excellent promise as a minimum invasive diagnostic tool for pH-related cellular mechanism studies, such as inflammation, cytotoxicity, drug resistance, carcinogenesis, stem cell differentiation and so on.

Unveil early-stage nanocytotoxicity by a label-free single cell pH nanoprobe.

Single-cell analysis is an emerging research area that aims to reveal delicate cellular status and underlying mechanisms by conquering the intercellular heterogeneity. Current single-cell research methods, however, are highly dependent on cell-destructive protocols and cannot sequentially display the progress of cellular events. A recently developed pH nanoprobe in our lab conceptually showed its ability to detect intracellular pH (pHi) without cell labeling or disruption. In the present study, we took the cytotoxicity of nanoparticles (NPs) as a typical example of cell heterogeneity, to testify the practicality of the pH nanoprobe in interpreting cell status. Three types of NPs (CeO2, TiO2, and SiO2) were employed to generate varied toxic effects. Results showed that the traditional assays - including cell viability, intracellular ROS generation, and mitochondrial inner membrane depolarization - not only failed to report the nanotoxicity accurately and timely, but also drew confusing or misleading conclusions. The pH nanoprobe revealed explicit pHi changes induced by the NPs, which corresponded well with the cell damages found by the transmission electron microscopic (TEM) imaging. Besides, our results unveiled an unexpectedly devastating effect of SiO2 NPs on cells during the early stage NP-cell interaction. The developed novel pH nanoprobe demonstrated a rapid sensing capability at single-cell resolution with minimum invasiveness. Therefore, it may become a promising alternative for a wide range of applications in areas such as single-cell research and precision medicine.

Evaluation of statistical techniques to normalize mass spectrometry-based urinary metabolomics data.

Human urine recently became a popular medium for metabolomics biomarker discovery because its collection is non-invasive. Sometimes renal dilution of urine can be problematic in this type of urinary biomarker analysis. Currently, various normalization techniques such as creatinine ratio, osmolality, specific gravity, dry mass, urine volume, and area under the curve are used to account for the renal dilution. However, these normalization techniques have their own drawbacks. In this project, mass spectrometry-based urinary metabolomic data obtained from prostate cancer (n = 56), bladder cancer (n = 57) and control (n = 69) groups were analyzed using statistical normalization techniques. The normalization techniques investigated in this study are Creatinine Ratio, Log Value, Linear Baseline, Cyclic Loess, Quantile, Probabilistic Quotient, Auto Scaling, Pareto Scaling, and Variance Stabilizing Normalization. The appropriate summary statistics for comparison of normalization techniques were created using variances, coefficients of variation, and boxplots. For each normalization technique, a principal component analysis was performed to identify clusters based on cancer type. In addition, hypothesis tests were conducted to determine if the normalized biomarkers could be used to differentiate between the cancer types. The results indicate that the determination of statistical significance can be dependent upon which normalization method is utilized. Therefore, careful consideration should go into choosing an appropriate normalization technique as no method had universally superior performance.

Accurate determination of drug-to-antibody ratio of interchain cysteine-linked antibody-drug conjugates by LC-HRMS.

Accurate determination of the drug-to-antibody ratio (DAR) of interchain cysteine-linked antibody-drug conjugates (ADCs) is challenging. High-resolution mass spectrometry (HRMS) analysis of the ADCs at the intact or subunit level provides a feasible way to measure the DAR. However, the measured DAR is usually lower than the true DAR because of the variation in ionization efficiency between different DAR species. In this work, we developed a novel standard-free HRMS method involving isotope-labeled payload conjugation, protease digestion, and liquid chromatography-HRMS (LC-HRMS) analysis for accurate determination of the DAR of the interchain cysteine-linked ADCs with cleavable or non-cleavable linkers. Isotope-labeled payload conjugations eliminated the structural and chemical differences between different DAR species and ensured that the drugs or payload-containing peptides could be separated from each other in the mass spectrometer. A papain digestion strategy for ADCs with cleavable linkers showed a DAR of 3.79, with a relative standard deviation (RSD) of 0.48 (n = 3). Similarly, the trypsin and chymotrypsin digestion strategy that is applicable to ADCs with non-cleavable linkers showed a DAR of 3.77 and an RSD of 0.86 (n = 3). The DAR determined by this method was consistent with the DAR of the ADCs that was measured by the UV/Vis method. This method will be very useful to researchers working in the field of ADC discovery and development. Graphical abstract.

Characterization of Positional Isomers of Interchain Cysteine Linked Antibody-Drug Conjugates by High-Resolution Mass Spectrometry.

Interchain cysteine linked antibody-drug conjugates (ADCs) are emerging therapeutic products that antagonize cancers. The toxic payloads are selectively linked to the interchain cysteines and generate heterogeneous mixtures of positional isomers. These positional isomers might contribute differently to the therapeutic efficacy because of the variation in conjugation stability, and thus they need to be well characterized. However, the characterization of the positional isomers of interchain cysteine linked ADCs is very challenging, mainly because of the high similarity between those isomers. In this research, we developed a novel mass spectrometry method for the characterization of positional isomers of interchain cysteine linked ADCs. The subunit analysis and the bottom-up analysis provided abundant information about the drug numbers and drug linking positions on each chain. Because the method can provide accurate data on drug linking numbers and positions on each chain, it will be very useful for researchers in cancer drug development and cancer treatment.

Current Trends in Cancer Biomarker Discovery Using Urinary Metabolomics: Achievements and New Challenges.

BACKGROUND: The development of effective screening methods for early cancer detection is one of the foremost challenges facing modern cancer research. Urinary metabolomics has recently emerged as a potentially transformative approach to cancer biomarker discovery owing to its noninvasive sampling characteristics and robust analytical feasibility. OBJECTIVE: To provide an overview of new developments in urinary metabolomics, cover the most promising aspects of hyphenated techniques in untargeted and targeted metabolomics, and to discuss technical and clinical limitations in addition to the emerging challenges in the field of urinary metabolomics and its application to cancer biomarker discovery. METHODS: A systematic review of research conducted in the past five years on the application of urinary metabolomics to cancer biomarker discovery was performed. Given the breadth of this topic, our review focused on the five most widely studied cancers employing urinary metabolomics approaches, including lung, breast, bladder, prostate, and ovarian cancers. RESULTS: As an extension of conventional metabolomics, urinary metabolomics has benefitted from recent technological developments in nuclear magnetic resonance, mass spectrometry, gas and liquid chromatography, and capillary electrophoresis that have improved urine metabolome coverage and analytical reproducibility. Extensive metabolic profiling in urine has revealed a significant number of altered metabolic pathways and putative biomarkers, including pteridines, modified nucleosides, and acylcarnitines, that have been associated with cancer development and progression. CONCLUSION: Urinary metabolomics presents a transformative new approach toward cancer biomarker discovery with high translational capacity to early cancer screening.

Simultaneous removal of ammonia and N-nitrosamine precursors from high ammonia water by zeolite and powdered activated carbon.

When adding sufficient chlorine to achieve breakpoint chlorination to source water containing high concentration of ammonia during drinking water treatment, high concentrations of disinfection by-products (DBPs) may form. If N-nitrosamine precursors are present, highly toxic N-nitrosamines, primarily N-nitrosodimethylamine (NDMA), may also form. Removing their precursors before disinfection should be a more effective way to minimize these DBPs formation. In this study, zeolites and activated carbon were examined for ammonia and N-nitrosamine precursor removal when incorporated into drinking water treatment processes. The test results indicate that Mordenite zeolite can remove ammonia and five of seven N-nitrosamine precursors efficiently by single step adsorption test. The practical applicability was evaluated by simulation of typical drinking water treatment processes using six-gang stirring system. The Mordenite zeolite was applied at the steps of lime softening, alum coagulation, and alum coagulation with powdered activated carbon (PAC) sorption. While the lime softening process resulted in poor zeolite performance, alum coagulation did not impact ammonia and N-nitrosamine precursor removal. During alum coagulation, more than 67% ammonia and 70%-100% N-nitrosamine precursors were removed by Mordenite zeolite (except 3-(dimethylaminomethyl)indole (DMAI) and 4-dimethylaminoantipyrine (DMAP)). PAC effectively removed DMAI and DMAP when added during alum coagulation. A combination of the zeolite and PAC selected efficiently removed ammonia and all tested seven N-nitrosamine precursors (dimethylamine (DMA), ethylmethylamine (EMA), diethylamine (DEA), dipropylamine (DPA), trimethylamine (TMA), DMAP, and DMAI) during the alum coagulation process.

Fate of nanoparticles during alum and ferric coagulation monitored using single particle ICP-MS.

In this study, aluminum sulfate, ferric sulfate, ferric chloride, and poly(diallyldimethylammonium chloride) (pDADMAC) coagulation removal of citrate-stabilized silver and gold nanoparticles (NPs) and uncoated titanium dioxide, cerium dioxide, and zinc oxide NPs was investigated using a single particle (SP) ICP-MS direct monitoring technique. Zone 2 (charge neutralization) coagulation was performed in river water and more commonly used Zone 4 (sweep floc) coagulation was performed in both river and lake water with environmentally relevant concentrations of selected NPs added. SP-ICP-MS was used to detect NP and dissolved species, characterize the size distribution, and quantify particle concentration as well as dissolved species before and after treatments. Other parameters including pH, dissolved organic carbon, turbidity, and UV254 absorbance were monitored to characterize treatment efficiency. Charge neutralization (Zone 2) coagulation resulted in 48-85% removal of citrate-stabilized NPs and 90-99% removal of uncoated NPs from river water. Sweep floc (Zone 4) coagulation in river water resulted in 36-94% removal of citrate-stabilized NPs and 91-99% removal of uncoated NPs both with and without polymer addition. Zone 4 coagulation conditions in lake water resulted in 77-98% removal of citrate-stabilized NPs and 59-96% removal of uncoated NPs without polymer. These results indicate that NP removal depends on NP surface and stability, the nature of the source water, and the coagulant type and approach.

Evaluation of thirteen haloacetic acids and ten trihalomethanes formation by peracetic acid and chlorine drinking water disinfection.

Free chlorine is a commonly used disinfectant in drinking water treatment. However, disinfection by-products (DBPs) are formed during water disinfection. Haloacetic acids (HAAs) and trihalomethanes (THMs) are two major groups of DBPs. Iodo-HAAs and iodo-THMs (I-HAAs and I-THMs) are formed during the disinfection of the water containing high levels of iodide and are much more toxic than their chlorinated and brominated analogs. Peracetic acid (PAA) is a strong antimicrobial disinfectant that is expected to reduce the formation of HAAs and THMs during disinfection. In this study, the formations of thirteen HAAs and ten THMs, including the iodinated forms, have been investigated during PAA disinfection and chlorination as the comparison. The DBP formations under different iodide concentrations, pHs, and contact times were systematically investigated. Two types of commercial PAAs containing different concentrations of PAA and hydrogen peroxide (H2O2) were studied. A solid-phase microextraction gas chromatography-mass spectrometry method was upgraded for THM analysis including I-THMs. HAAs were analyzed by following a recently developed high performance ion chromatography-tandem mass spectrometry method. Results show that the ratio of PAA and H2O2 concentration significantly affect the formation of I-THMs and I-HAAs. During PAA disinfection with lower PAA than H2O2, no detectable levels of THMs and HAAs were observed. During PAA disinfection with higher PAA than H2O2, low levels of monoiodoacetic acid, diiodoacetic acid, and iodoform were formed, and these levels were enhanced with the increase of iodide concentration. No significant quantities of chloro- or bromo-THMs and HAAs were formed during PAA disinfection treatment.

Effect of oxidant demand on the release and degradation of microcystin-LR from Microcystis aeruginosa during oxidation.

In this research, the release and degradation of intracellular microcystin-LR (MC-LR) due to oxidation of Microcystis aeruginosa (M. aeruginosa) was examined kinetically. Brief exposure to free chlorine with no measureable oxidant exposure was demonstrated to be sufficient to induce rapid release of intracellular MC-LR from M. aeruginosa. Thus, in a water treatment plant, there is currently no level of prechlorination that can be assumed to be safe, since very low preoxidation prior to filtration and no measureable free chlorine residual may still observe the release and buildup of extracellular MC-LR. Higher chlorine dosages resulting in a measureable exposure or CT (concentration times contact time) cause more rapid release and oxidation of the intracellular toxins. Further, the rate of release of MC-LR with intermediate oxidant dosages were shown to be initially rapid, but then slowed to a lower release rate due to an as yet undetermined mechanism. While free chlorine was reactive with the extracellular MC-LR, the monochloramine resulting from the consumption of the free chlorine by ammonia was not. Consideration of the ammonia concentration and the chlorine dosage relative to the chlorination breakpoint dosages is important for utilities assessing the impact of prechlorination of water containing cyanobacteria. MC-LR, once released, was rapidly oxidized by permanganate resulting in only negligible buildup of extracellular toxins.

Local pH Monitoring of Small Cluster of Cells using a Fiber-Optic Dual-Core Micro-Probe.

Biological studies of tissues and cells have enabled numerous discoveries, but these studies still bear potential risks of invalidation because of cell heterogeneity. Through high-accuracy techniques, recent studies have demonstrated that discrepancies do exist between the results from low-number-cell studies and cell-population-based results. Thus the urgent need to re-evaluate key principles on limited number of cells has been provoked. In this study, a novel designed dual-core fiber-optic pH micro-probe was fabricated and demonstrated for niche environment pH sensing with high spatial resolution. An organic-modified silicate (OrMoSils) sol-gel thin layer was functionalized by entrapping a pH indicator, 2', 7'-Bis (2-carbonylethyl)-5(6)-carboxyfluorescein (BCECF), on a ~70 µm sized probe tip. Good linear correlation between fluorescence ratio of I560 nm/I640 nm and intercellular pH values was obtained within a biological-relevant pH range from 6.20 to 7.92 (R2 = 0.9834), and with a pH resolution of 0.035 ± 0.005 pH units. The probe's horizontal spatial resolution was demonstrated to be less than 2mm. Moreover, the probe was evaluated by measuring the localized extracellular pH changes of cultured human lung cancer cells (A549) when exposed to titanium dioxide nanoparticles (TiO2 NPs). Results showed that the probe has superior capability for fast, local, and continual monitoring of a small cluster of cells, which provides researchers a fast and accurate technique to conduct local pH measurements for cell heterogeneity-related studies.

In vitro stimulation of vascular endothelial growth factor by borate-based glass fibers under dynamic flow conditions.

Bioactive borate glass has been recognized to have both hard and soft tissue repair and regeneration capabilities through stimulating both osteogenesis and angiogenesis. However, the underlying biochemical and cellular mechanisms remain unclear. In this study, dynamic flow culturing modules were designed to simulate the micro-environment near the vascular depletion and hyperplasia area in wound-healing regions, thus to better investigate the mechanisms underlying the biocompatibility and functionality of borate-based glass materials. Glass fibers were dosed either upstream or in contact with the pre-seeded cells in the dynamic flow module. Two types of borate glasses, doped with (1605) or without (13-93B3) CuO and ZnO, were studied along with the silicate-based glass, 45S5. Substantial fiber dissolution in cell culture medium was observed, leading to the release of ions (boron, sodium and potassium) and the deposition of a calcium phosphate phase. Different levels of vascular endothelial growth factor secretion were observed from cells exposed to these three glass fibers, and the copper/zinc containing borate 1605 fibers exhibited the most positive influence. These results indicate that dynamic studies of in vitro bioactivity provide useful information to understand the in vivo response to bioactive borate glasses.

Development of a high-performance liquid chromatography - Tandem mass spectrometry urinary pterinomics workflow.

Pteridines have evoked considerable interest from the scientific community owing to their prominent roles in human health and disease. The availability of analytical methodologies suitable for comprehensive pteridine profiling, termed here as "pterinomics", has been limited by inconsistent sample preparation and the exclusion of lesser studied pteridine derivatives. In response, the present study describes a new pterinomics workflow using a high-performance liquid chromatography - tandem mass spectrometry (HPLC-MS/MS) methodology for the simultaneous analysis of 15 pteridine derivatives including four structural isomers, marking the largest quantitative pteridine panel that has been studied to-date. The validated method possessed excellent sensitivity with method detection limits (0.025 µg L(-1) to 0.5 µg L(-1)) that were comparable or superior to existing techniques. Spiked recovery studies demonstrated the technique was both accurate (88-112%) and precise (RSD: 0-6%). A comparative study of commonly used oxidative pretreatments, including triiodide, permanganate, and manganese dioxide, revealed that the oxidative mechanisms were inefficient, complex, and concentration dependent. Finally, 50 clinical urine specimens were examined with the new technique wherein 10 pteridine derivatives were quantified and population ranges have been given. This technique can be used to examine pteridine molecular epidemiology and biochemistry to support related research applications, and may further be readily extended to include additional pteridine derivatives and biological matrices for specific applications.

N-nitrosamine formation by monochloramine, free chlorine, and peracetic acid disinfection with presence of amine precursors in drinking water system.

In this study, the formation of eight N-nitrosamines, N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine, N-nitrosomethylamine, N-nitrosodi-n-propylamine, N-nitrosodi-n-butylamine, N-Nitrosopiperidine, N-Nitrosopyrrolidine, N-Nitrosomorpholine, were systematically evaluated with respect to seven N-nitrosamine precursors (dimethylamine, trimethylamine, 3-(dimethylaminomethyl)indole, 4-dimethylaminoantipyrine, ethylmethylamine, diethylamine, dipropylamine) and three disinfectants (monochloramine, free chlorine, peracetic acid) under variable dosages, exposure times, and pH in a drinking water system. Without the presence of the seven selected N-nitrosamine precursors N-nitrosamine formation was not observed under any tested condition except very low levels of N-Nitrosopyrrolidine under some conditions. With selected N-nitrosamine precursors present N-nitrosamines formed at different levels under different conditions. The highest N-nitrosamine formation was NDMA with a maximum concentration of 1180 ng/L by monochloramine disinfection with precursors present; much lower levels of N-nitrosamines were formed by free chlorine disinfection; and no detectable level of N-nitrosamines were observed by peracetic acid disinfection except low level of N-Nitrosodi-n-propylamine under some conditions. NDMA formation was not affected by pH while four other N-nitrosamine formations were slightly affected by sample pH tested between 7 and 9, with formation decreasing with increasing pH. Monochloramine exposure time study displayed fast formation of N-nitrosamines, largely formed in four hours of exposure and maximized after seven days. This was a systematic study on the N-nitrosamine formation with the seven major N-nitrosamine precursors presence and absence under different conditions, including peracetic acid disinfection which has not been studied elsewhere.

Detection of zinc oxide and cerium dioxide nanoparticles during drinking water treatment by rapid single particle ICP-MS methods.

Nanoparticles (NPs) entering water systems are an emerging concern as NPs are more frequently manufactured and used. Single particle inductively coupled plasma-mass spectrometry (SP-ICP-MS) methods were validated to detect Zn- and Ce-containing NPs in surface and drinking water using a short dwell time of 0.1 ms or lower, ensuring precision in single particle detection while eliminating the need for sample preparation. Using this technique, information regarding NP size, size distribution, particle concentration, and dissolved ion concentrations was obtained simultaneously. The fates of Zn- and Ce-NPs, including those found in river water and added engineered NPs, were evaluated by simulating a typical drinking water treatment process. Lime softening, alum coagulation, powdered activated carbon sorption, and disinfection by free chlorine were simulated sequentially using river water. Lime softening removed 38-53 % of Zn-containing and ZnO NPs and >99 % of Ce-containing and CeO2 NPs. Zn-containing and ZnO NP removal increased to 61-74 % and 77-79 % after alum coagulation and disinfection, respectively. Source and drinking water samples were collected from three large drinking water treatment facilities and analyzed for Zn- and Ce-containing NPs. Each facility had these types of NPs present. In all cases, particle concentrations were reduced by a minimum of 60 % and most were reduced by >95 % from source water to finished drinking water. This study concludes that uncoated ZnO and CeO2 NPs may be effectively removed by conventional drinking water treatments including lime softening and alum coagulation.

Single particle ICP-MS characterization of titanium dioxide, silver, and gold nanoparticles during drinking water treatment.

One of the most direct means for human exposure to nanoparticles (NPs) released into the environment is drinking water. Therefore, it is critical to understand the occurrence and fate of NPs in drinking water systems. The objectives of this study were to develop rapid and reliable analytical methods and apply them to investigate the fate and transportation of NPs during drinking water treatments. Rapid single particle ICP-MS (SP-ICP-MS) methods were developed to characterize and quantify titanium-containing, titanium dioxide, silver, and gold NP concentration, size, size distribution, and dissolved metal element concentration in surface water and treated drinking water. The effectiveness of conventional drinking water treatments (including lime softening, alum coagulation, filtration, and disinfection) to remove NPs from surface water was evaluated using six-gang stirrer jar test simulations. The selected NPs were nearly completely (97 ± 3%) removed after lime softening and alum coagulation/activated carbon adsorption treatments. Additionally, source and drinking waters from three large drinking water treatment facilities utilizing similar treatments with the simulation test were collected and analyzed by the SP-ICP-MS methods. Ti-containing particles and dissolved Ti were present in the river water samples, but Ag and Au were not present. Treatments used at each drinking water treatment facility effectively removed over 93% of the Ti-containing particles and dissolved Ti from the source water.

Urinary metallomics as a novel biomarker discovery platform: Breast cancer as a case study.

BACKGROUND: Urinary metallomics is presented here as a new "omics" approach that aims to facilitate personalized cancer screening and prevention by improving our understanding of urinary metals in disease. METHODS: Twenty-two urinary metals were examined with inductively-coupled plasma-mass spectrometry in 138 women newly diagnosed with breast cancer and benign conditions. Urinary metals from spot urine samples were adjusted to renal dilution using urine specific gravity. RESULTS: Two urinary metals, copper (P-value=0.036) and lead (P-value=0.003), were significantly increased in the urine of breast cancer patients. A multivariate model that comprised copper, lead, and patient age afforded encouraging discriminatory power (AUC: 0.728, P-value<0.0005), while univariate models of copper (61.7% sensitivity, 50.0% specificity) and lead (76.6% sensitivity, 51.2% specificity) at optimized cutoff thresholds compared favorably with other breast cancer diagnostic modalities such as mammography. Correlations found among various metals suggested potential geographic and dietary influences on the urine metallome that warrant further investigation. CONCLUSIONS: This proof-of-concept work introduces urinary metallomics as a noninvasive, potentially transformative "omics" approach to early cancer detection. Urinary copper and lead have also been preliminarily identified as potential breast cancer biomarkers.

Physicochemical insights of irradiation-enhanced hydroxyl radical generation from ZnO nanoparticles.

The widespread use of zinc oxide nanoparticles (ZnO NPs) has raised environmental and human health concerns owing to their significant cytotoxicity. Although their cytotoxic effects have been associated with reactive oxygen species (ROS), the physicochemical mechanism underlying this phenomenon remains poorly understood. In this study, the physicochemical properties of ZnO NPs were systematically investigated in relation to their effect on ROS generation. Factors that were found to affect hydroxyl radical (˙OH) generation included: NP concentration, irradiation, NP hydrodynamic size, localized pH, ionic strength, NP zeta-potential, and dissolved oxygen levels. The mechanism by which ˙OH was generated under alkaline conditions was found to obey first-order reaction kinetics that followed the conversion of OH- anions and dissolved O2 to ˙OH. Based on these findings, we propose that ZnO NP cytotoxicity involves ˙OH adsorption to the nanoparticle surface, creating a highly localized source of ROS capable of potentiating oxidative damage to cellular structures. This hypothesis was evaluated with time-resolved intracellular calcium [Ca] i imaging that irradiated ZnO NPs triggered cytoplasmic calcium influxes and facilitated nuclear degradation. Together these findings present a novel physicochemical mechanism for ˙OH generation from ZnO NPs with significant implications for nanoparticle cytotoxicity and their relation to human health.

Biomarker analysis for oncology.

Cancer biomarkers are biological, chemical or biophysical entities that are present in tumor tissues or body fluids which give valuable information about current and future behavior of cancer. This review discusses the applicability of biomarkers in different stages of cancer from cancer risk assessment to recurrence. In medical practice, biomarkers can be helpful in finding out one's potential cancer risk, confirming whether or not one is already affected with a particular type of cancer, to which drug will the cancer respond best and in what doses should it be administered, the effectiveness of the treatment and whether the cancer will recur. Although biomarker discovery and validation is a very challenging process, when considering its applications and advantages, it is well worth the effort.