A fibroblast activation protein α-activatable nanoagent co-delivering diethyldithiocarbamate and copper for tumor therapy and imaging.

Disulfiram (DSF), an FDA-approved drug for treating alcoholism, has been verified with Cu2+-dependent anticancer activity by forming Cu(DTC)2, the complex of one of its metabolites diethyldithiocarbamate (DTC) and Cu2+. Nevertheless, the antitumor effect is limited by insufficient Cu(DTC)2 formation in suit and off-target system toxicity. Herein, we developed a fibroblast activation protein α (FAPα) activatable nanoagent (HfD-HID-Cu) for co-delivery of DTC polymeric prodrug and exogenous Cu2+ to achieve enhanced cancer-specific therapy and activatable in situ fluorescence imaging meanwhile. HfD-HID-Cu was simply constructed through the co-assembly of the DTC polymeric prodrug (HA-fap-DTC) and the copper-loaded IR808-conjugated polymer (HA-IR-DPA-Cu), which could serve as the "OFF-to-ON" switch for chemotherapy and fluorescence. With the high expression of FAPα in tumor tissues, HA-fap-DTC could be activated specifically to release DTC, while maintaining inactive in normal tissues. The liberated DTC within tumor tissues could contend for Cu2+ from HA-IR-DPA-Cu, resulting in the formation of highly cytotoxic Cu(DTC)2in situ for chemotherapy, concomitant with the fluorescence recovery of cyanine dye for tumor imaging. This work provides an effective strategy for co-delivery of DTC prodrug and Cu2+ for tumor theranostic with improved selectivity and minimal side effects. STATEMENT OF SIGNIFICANCE: DSF-based antitumor therapy is highly dependent on Cu2+. However, the non-synchronous distribution of DSF/DTC and Cu2+ in tumor tissues attenuates the antitumor efficacy. The insufficient Cu(DTC)2 formation in suit and off-target distribution greatly limit the anti-tumor application. This study provides a nanoagent for co-delivery of DTC polymeric prodrug and Cu2+ by simple co-assembly to achieve their synchronous tumor distribution. It can be selectively activated by FAPα, forming cytotoxic Cu(DTC)2in suit for tumor-specific chemotherapy and reducing the systemic toxicity. In addition to chemotherapy, the nanoagent can emit fluorescence under the sequential triggering of FAPα and released DTC for tumor imaging. Overall, this study renders a promising strategy for improved Cu(DTC)2-based antitumor therapy and imaging.

Evaluation of Nitric Oxide-Donating Properties of 11H-indeno[1,2-b]quinoxalin-11-one Oxime (IQ-1) by Electron Paramagnetic Resonance Spectroscopy.

IQ-1 (11H-indeno[1,2-b]quinoxalin-11-one oxime) is a specific c-Jun N-terminal kinase (JNK) inhibitor with anticancer and neuro- and cardioprotective properties. Because aryloxime derivatives undergo cytochrome P450-catalyzed oxidation to nitric oxide (NO) and ketones in liver microsomes, NO formation may be an additional mechanism of IQ-1 pharmacological action. In the present study, electron paramagnetic resonance (EPR) of the Fe2+ complex with diethyldithiocarbamate (DETC) as a spin trap and hemoglobin (Hb) was used to detect NO formation from IQ-1 in the liver and blood of rats, respectively, after IQ-1 intraperitoneal administration (50 mg/kg). Introducing the spin trap and IQ-1 led to signal characteristics of the complex (DETC)2-Fe2+-NO in rat liver. Similarly, the introduction of the spin trap components and IQ-1 resulted in an increase in the Hb-NO signal for both the R- and the T-conformers in blood samples. The density functional theory (DFT) calculations were in accordance with the experimental data and indicated that the NO formation of IQ-1 through the action of superoxide anion radical is thermodynamically favorable. We conclude that the administration of IQ-1 releases NO during its oxidoreductive bioconversion in vivo.

2-Cyanoethyl dimethyldithiocarbamate, a new contact allergen found in accelerator-free nitrile gloves.

BACKGROUND: Allergic contact dermatitis (ACD) from rubber glove usage is usually caused by rubber additives such as the accelerators. However, in analyses of the suspected gloves, ordinary rubber allergens are not always found. Accelerator-free rubber gloves are available, but some patients with accelerator allergy do not tolerate them and might also be patch test positive to them. OBJECTIVES: To identify and chemically characterize a new allergen, 2-cyanoethyl dimethyldithiocarbamate (CEDMC), in rubber gloves. We describe two patient cases: patient 1 that led us to the identification of CEDMC and patient 2 with occupational ACD caused by CEDMC. METHODS: The patients were examined with patch testing including baseline and rubber series, and their own rubber gloves. High-performance liquid chromatography (HPLC) was used for chemical analysis of rubber gloves. The allergen was synthesized and identified by nuclear magnetic resonance, mass spectrometry and infrared spectrometry, and tested on patient 2. RESULTS: CEDMC was identified by HPLC in a nitrile glove associated with hand eczema in patient 1. Patient 2 whose nitrile gloves contained CEDMC was patch test positive to CEDMC. CONCLUSIONS: CEDMC is a new contact allergen in nitrile gloves and probably forms during vulcanization from residual monomer acrylonitrile and rubber additives.

Synergistic eradicating impact of 5-fluouracil with FeO nanoparticles-diethyldithiocarbamate in colon cancer spheroids.

Background: Cancer stem cells' (CSCs) resistance to 5-fluorouracil (Fu), which is the main obstacle in treating colon cancer (CC), can be overcome by ferroptosis. The latter, herein, can be triggered by FeO nanoparticles (inducer of iron accumulation) and diethyldithiocarbamate-inhibited glutathione system and aldehyde dehydrogenase (ALDH1A1-maintained stemness, therapeutic resistance and metastasis). Materials & methods: Nanocomplex of FeO nanoparticles and diethyldithiocarbamate (FD) was used in combination with Fu to investigate its potential synergistic anti-CSC influence using CC spheroid models. Results: In Fu + FD-treated spheroids, the strongest growth inhibition, the highest cell death percentage, and the lowest CD133+-CSCs percentage and stemness gene expressions (e.g., drug efflux transporter), and the strongest antimetastatic effect were recorded with high synergistic indexes. Conclusion: Fu + FD represents effective combination therapy for chemoresistant CC cells.

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Spin Trapping of Nitric Oxide by Hemoglobin and Ferrous Diethyldithiocarbamate in Model Tumors Differing in Vascularization.

Animal tumors serve as reasonable models for human cancers. Both human and animal tumors often reveal triplet EPR signals of nitrosylhemoglobin (HbNO) as an effect of nitric oxide formation in tumor tissue, where NO is complexed by Hb. In search of factors determining the appearance of nitrosylhemoglobin (HbNO) in solid tumors, we compared the intensities of electron paramagnetic resonance (EPR) signals of various iron-nitrosyl complexes detectable in tumor tissues, in the presence and absence of excess exogenous iron(II) and diethyldithiocarbamate (DETC). Three types of murine tumors, namely, L5178Y lymphoma, amelanotic Cloudman S91 melanoma, and Ehrlich carcinoma (EC) growing in DBA/2 or Swiss mice, were used. The results were analyzed in the context of vascularization determined histochemically using antibodies to CD31. Strong HbNO EPR signals were found in melanoma, i.e., in the tumor with a vast amount of a hemorrhagic necrosis core. Strong Fe(DETC)2NO signals could be induced in poorly vascularized EC. In L5178Y, there was a correlation between both types of signals, and in addition, Fe(RS)2(NO)2 signals of non-heme iron-nitrosyl complexes could be detected. We postulate that HbNO EPR signals appear during active destruction of well-vascularized tumor tissue due to hemorrhagic necrosis. The presence of iron-nitrosyl complexes in tumor tissue is biologically meaningful and defines the evolution of complicated tumor-host interactions.

Identification, Isolation, and Characterization of a Novel Degradation Impurity of Busulfan Using Preparative Chromatography, NMR, and LC-MS.

BACKGROUND: Busulfan is the most effective medication for treating chronic myelogenous or granulocytic leukemia because it has cytotoxic properties that harm or kill hematopoietic cells. It cannot absorb light in the Ultraviolet range due to its structure. Because of this, it is very challenging to quantify using traditional HPLC coupled with UV/Photodiode Array detectors. So, using sodium diethyldithiocarbamate, a derivatization method was developed to quantify related impurities. A significant unknown impurity was identified in derivatized samples of busulfan and a noticeably high percentage level was discovered during routine drug testing. OBJECTIVE: We aimed to isolate, and characterize the unknown impurity observed in the samples and to identify its root cause. METHODS: Preparative HPLC was used to isolate the unidentified, derivatized impurity, and 1H NMR, 13C NMR, and MS were used to decipher its structural components. RESULTS: The spectral characterization data analysis showed that the unknown impurity was related to busulfan. Additionally, it was noted that the impurity developed as a result of the residual buffer used to prepare the derivatizing reagent. CONCLUSION: The isolated impurity was found to be same as comparable to that found in busulfan drug substances, according to the results of the characterization tools. An alternative method of reagent preparation was optimized and deemed satisfactory because the buffer used in reagent preparation is the only factor contributing to the formation of impurities. HIGHLIGHTS: Using cutting-edge analytical characterization tools, it was possible to explain the structural characteristics of an unknown impurity and discover that it was a novel impurity, which undoubtedly contributes to the comprehension of drug substance reaction properties.

Hydroxyethyl starch stabilized copper-diethyldithiocarbamate nanocrystals for cancer therapy.

Cancer stem cells (CSCs) have been recognized as the culprit for tumor progression, treatment resistance, metastasis, and recurrence while redox homeostasis represents the Achilles' Heel of CSCs. However, few drugs or formulations that are capable of elevating oxidative stress have achieved clinical success for eliminating CSCs. Here, we report hydroxyethyl starch stabilized copper-diethyldithiocarbamate nanoparticles (CuET@HES NPs), which conspicuously suppress CSCs not only in vitro but also in numerous tumor models in vivo. Furthermore, CuET@HES NPs effectively inhibit CSCs in fresh tumor tissues surgically excised from hepatocellular carcinoma patients. Mechanistically, we uncover that hydroxyethyl starch stabilized copper-diethyldithiocarbamate nanocrystals via copper­oxygen coordination interactions, thereby promoting copper-diethyldithiocarbamate colloidal stability, cellular uptake, intracellular reactive oxygen species production, and CSCs apoptosis. As all components are widely used in clinics, CuET@HES NPs represent promising treatments for CSCs-rich solid malignancies and hold great clinical translational potentials. This study has critical implications for design of CSCs targeting nanomedicines.

Anti-metastatic breast cancer potential of novel nanocomplexes of diethyldithiocarbamate and green chemically synthesized iron oxide nanoparticles.

Mortality rate of metastatic breast cancer is linked to cancer stem cells (CSCs)' aggressive features (chemoresistance to apoptosis and redox imbalance). Therefore, unique dual therapeutic strategy compacts CSCs with inducing oxidative stress-mediated nonapoptosis (ferroptosis), confers effective malignant tumor eradication. Diethyldithiocarbamate (DDC) is a potent inhibitor of CSC aldehyde dehydrogenase and lowers glutathione (GSH) which aggravate iron-dependent ferroptosis. Herein, nanoformulations of DDC with green chemically synthesized ferrous oxide nanoparticles (FeO NPs) and ferric oxide (Fe2O3 NPs) were prepared. Due to nanoparticle characters and synergistic effect between iron oxide NPs and DDC, nanocomplexes (DFeO NPs and DFe2O3 NPs, respectively) exhibited the strongest anti-metastatic cancer potency in vitro. Because of corresponding iron oxide nature, DFeO NPs demonstrated better therapeutic efficacy than DFe4O3 NPs, in mammary tumor liver metastasis-bearing mice, in terms of tumor size, histological analysis, immunostaining % of ki-67+ and caspase 3+, and gene expression of p53 and BCl2. The potent anti-tumor effect of DFeO nanocomplex is attributed to the maximum elevation of reactive oxygen species and lipid peroxidation (ferroptosis hall marker) with severe depletion of GSH and Nrf2 selectively in both tumor tissues, causing CSC eradication with halting metastatic activity. The latters were confirmed by lowering CD44+ % and gene expression of HIF-α, ß-catenin, Notch, ABCG2-mediated chemoresistance, and MMP9 with diminishing liver tumor marker. Moreover, this nanocomplex did not cause any abnormal alterations in histological and biochemical parameters, compared to healthy group. Therefore, the selective apoptotic and ferroptotic with anti-CSC effects of DFeO NPs open new safe avenue for metastatic tumor therapy.

Disulfiram oxy-derivatives induce entosis or paraptosis-like death in breast cancer MCF-7 cells depending on the duration of treatment.

BACKGROUND: Dithiocarbamates and derivatives (including disulfiram, DSF) are currently investigated as antineoplastic agents. We have revealed earlier the ability of hydroxocobalamin (vitamin В12b) combined with diethyldithiocarbamate (DDC) to catalyze the formation of highly cytotoxic oxidized derivatives of DSF (DSFoxy, sulfones and sulfoxides). METHODS: Electron and fluorescent confocal microscopy, molecular biology and conventional biochemical techniques were used to study the morphological and functional responses of MCF-7 human breast cancer cells to treatment with DDC and B12b alone or in combination. RESULTS: DDC induces unfolded protein response in MCF-7 cells. The combined use of DDC and B12b causes MCF-7 cell death. Electron microscopy revealed the separation of ER and nuclear membranes, leading to the formation of both cytoplasmic and perinuclear vacuoles, with many fibers inside. The process of vacuolization coincided with the appearance of ER stress markers, a marked damage to mitochondria, a significant inhibition of 20S proteasome, and actin depolimerization at later stages. Specific inhibitors of apoptosis, necroptosis, autophagy, and ferroptosis did not prevent cell death. A short- time (6-h) exposure to DSFoxy caused a significant increase in the number of entotic cells. CONCLUSIONS: These observations indicate that MCF-7 cells treated with a mixture of DDC and B12b die by the mechanism of paraptosis. A short- time exposure to DSFoxy caused, along with paraptosis, a significant activation of the entosis and its final stage, lysosomal cell death. GENERAL SIGNIFICANCE: The results obtained open up opportunities for the development of new approaches to induce non-apoptotic death of cancer cells by dithiocarbamates.

Sphingomyelin-based PEGylation Cu (DDC)2 liposomes prepared via the dual function of Cu2+ for cancer therapy: Facilitating DDC loading and exerting synergistic antitumor effects.

The old alcohol-aversion drug disulfiram (DSF) has aroused wide attention as a drug repurposing strategy in terms of cancer therapy because of the high antitumor efficacy in combination with copper ion. However, numerous defects of DSF (e.g., the short half-life and acid instability) have limited the application in cancer treatment. Cu (DDC)2, the complex of diethyldithiocarbamate (DDC, DSF metabolite) and Cu2+, have been proven as the vital active component on cancer, which have aroused the attention of researchers from DSF to Cu (DDC)2. However, the poor water solubility of Cu (DDC)2 increase more difficulties to the treatment and in-depth investigations of Cu (DDC)2. In this study, sphingomyelin (SM)-based PEGylated liposomes (SM/Chol/DSPE-mPEG2000 (55:40:5, mole%)) were produced as the carriers for Cu (DDC)2 delivery to enhance the water solubility. DDC was added to Cu-containing liposomes with a higher encapsulation efficiency of more than 90%, and it reacted with Cu2+ to synthesize Cu (DDC)2. Due to the high phase transition temperature of SM and strong intermolecular hydrogen bonds with cholesterol, SM-based liposomes would be conducive to enhancing the stability of Cu (DDC)2 and preventing drug leakage during delivery. As proven by pharmacokinetic studies, loading Cu (DDC)2 into liposomes improve bioavailability, and the area under the curve (AUC0-t) and the mean elimination half-life (t1/2) increased 1.9-time and 1.3-time to those of free Cu (DDC)2, respectively. Furthermore, the anticancer effect of Cu (DDC)2 was enhanced by the liposomal encapsulation, thus resulting in remarkable cell apoptosis in vitro and a tumor-inhibiting rate of 77.88% in vivo. Thus, it was concluded that Cu (DDC)2 liposomes could be promising in cancer treatment.

Comparison Studies on Several Ligands Used in Determination of Cd(II) in Rice by Flame Atomic Absorption Spectrometry after Ultrasound-Assisted Dispersive Liquid-Liquid Microextraction.

Ligands plays an important role in the extraction procedures for the determination of cadmium in rice samples by using flame atomic absorption spectrometry (FAAS). In the present study, comparative evaluation of 10 commercially available ligands for formation of Cd(II)-ligand complex and determination of cadmium in rice samples by ultrasound-assisted dispersive liquid-liquid microextraction (UADLLME) combined with FAAS was developed. Sodium diethyldithiocarbamate (DDTC) provided a high distribution coefficient as well as a good absorbance signal, therefore DDTC was used as a ligand in UADLLME. A low density and less toxic solvent, 1-heptanol, was used as the extraction solvent and ethanol was used as the disperser solvent. In addition, the experimental conditions of UADLLME were optimized in standard solution first and then applied in rice, such as the type and volume of extractant and dispersant, pH, extraction time, and temperature. Under the optimal experimental conditions, the detection limit (3σ) was 0.69 µg/L for Cd(II). The proposed method was applied for the determination of Cd(II) in three different rice samples (polished rice, brown rice, and glutinous rice), the recovery test was carried out, and the results ranged between 96.7 to 113.6%. The proposed method has the advantages of simplicity, low cost, and accurate and was successfully applied to analyze Cd(II) in rice.

Diethyldithiocarbamate/silk fibroin/polyethylene oxide nanofibrous for cancer therapy: Fabrication, characterization and in vitro evaluation.

Cancer has become a serious disease threatening human health. To tackle this issue, developing the existing potent anticancer drugs is critical to reducing the time and cost associated with creating a new drug from scratch. Diethyldithiocarbamate (DDC) - an anticancer drug- has received considerable attention due to its selectivity and reactivity. In this study, we prepared a nanofibrous matrix from silk fibroin/polyethylene oxide loaded with diethyldithiocarbamate (DDC@SF/PEO) from an aqueous solution via an electrospinning process. Upon DDC incorporation, the nanofiber's diameter has increased from 450 nm (SF/PEO) to 1202 nm (DDC@SF/PEO) confirming the successful incorporation of DDC. Furthermore, the hydrophobicity of DDC@SF/PEO nanofibrous matrix was improved by turning SF structure from random coil (silk I) to ß-sheet (silk II) through ethanol vapor treatment. Biocompatibility of DDC@SF/PEO nanofibrous matrix on human normal cells (Wi-38) showed it was safe and the apoptosis-mediated anticancer activity of DDC was enhanced. Thus, loading DDC on SF/PEO nanofibrous matrix is the key descriptor for enhanced anticancer efficacy of DDC. Considering the all-aqueous and simplistic process, the DDC@SF/PEO nanofibrous matrix could be a promising candidate for cancer treatment applications.

Surface Decoration via Physical Interaction of Cupric Diethyldithiocarbamate Nanocrystals and Its Impact on Biodistribution and Tumor Targeting.

The vascular wall is the first physiologic barrier that circulating nanoparticles (NPs) encounter, which also is a key biological barrier to cancer drug delivery. NPs can continually scavenge the endothelium for biomarkers of cancer, and the chance of NPs' extravasation into the tumors can be enhanced. Here, we envision P-selectin as a target for specific delivery of drug nanocrystals to tumors. The cupric diethyldithiocarbamate nanocrystals (CuET NCs) were first prepared by an antisolvent method, and then nanocrystals were coated with fucoidan via physical interaction. The fucoidan-coated CuET nanocrystals (CuET@Fuc) possess high drug loading and have the ability to interact with human umbilical vein endothelial cells expressing P-selectin, which transiently enhances the endothelial permeability and facilitates CuET@Fuc extravasation from the peritumoral vascular to achieve higher tumor accumulation of drugs than bare CuET NCs. The CuET NC shows poorer anticancer efficacy than CuET@Fuc at the same dose of CuET. Upon repeated dosing of CuET@Fuc for 2 weeks, no mortality was observed in treated melanoma-bearing mice, while the mortality in the control group and excipient-treated groups reached 23%. The growth rate of melanoma in the CuET@Fuc-treated group was significantly lower than those in other groups. Furthermore, an acute toxicity study revealed that CuET@Fuc is a safe formulation for cancer treatment.

A PDA-DTC/Cu-MnO2 nanoplatform for MR imaging and multi-therapy for triple-negative breast cancer treatment.

Herein, a multi-functional nanoplatform (PDA-DTC/Cu-MnO2) was established, which has been employed for MR imaging-guided multi-therapy (CDT, PTT and chemotherapy) for cancer treatment. The in vitro and in vivo results confirmed that the biocompatible nanoplatform could significantly induce tumor cell death and inhibit tumor growth.

A bismuth diethyldithiocarbamate compound induced apoptosis via mitochondria-dependent pathway and suppressed invasion in MCF-7 breast cancer cells.

Interest in bismuth(III) dithiocarbamate complexes as potential drug candidates is increasing due to their low toxicity compared to other group 15 elements (pnictogen) of the periodic table. Bismuth dithiocarbamate compounds have been reported to induce greater cytotoxicity in various human carcinoma cancer cell lines. Using various in vitro cancer-related assays, we investigated the antiproliferative activity of bismuth diethyldithiocarbamate, denoted as 1, against the MCF-7 human breast adenocarcinoma cell line and the effect on genes that may be involved in antiproliferation, apoptosis, DNA fragmentation, invasion and polyubiquitination functions. In general, 1 exhibited high cytotoxicity in MCF-7 cells, with an IC50 of 1.26 ± 0.02 µM, by inducing the intrinsic apoptotic pathway, as ascertained by measurements of intracellular reactive oxygen species (ROS), caspase activity, the amount of cytochrome c released and the extent of DNA fragmentation and by staining assays that reveal apoptotic cells. In addition, 1 significantly attenuated cell invasion and modulated several cancer-related genes, including PLK2, FIGF, FLT4, PARP4, and HDAC11, as determined via gene expression analysis. The NF-κB signaling pathway was inhibited by 1 upon the activation of Lys48- and Lys63-linked polyubiquitination, thus leading to its degradation via the proteasome. Overall, 1 has the potential to act as an antiproliferative agent and a proteasome inhibitor in estrogen-positive breast cancer.

Seesaw conformations of Npl4 in the human p97 complex and the inhibitory mechanism of a disulfiram derivative.

p97, also known as valosin-containing protein (VCP) or Cdc48, plays a central role in cellular protein homeostasis. Human p97 mutations are associated with several neurodegenerative diseases. Targeting p97 and its cofactors is a strategy for cancer drug development. Despite significant structural insights into the fungal homolog Cdc48, little is known about how human p97 interacts with its cofactors. Recently, the anti-alcohol abuse drug disulfiram was found to target cancer through Npl4, a cofactor of p97, but the molecular mechanism remains elusive. Here, using single-particle cryo-electron microscopy (cryo-EM), we uncovered three Npl4 conformational states in complex with human p97 before ATP hydrolysis. The motion of Npl4 results from its zinc finger motifs interacting with the N domain of p97, which is essential for the unfolding activity of p97. In vitro and cell-based assays showed that the disulfiram derivative bis-(diethyldithiocarbamate)-copper (CuET) can bypass the copper transporter system and inhibit the function of p97 in the cytoplasm by releasing cupric ions under oxidative conditions, which disrupt the zinc finger motifs of Npl4, locking the essential conformational switch of the complex.

Copper(II)-disulfiram loaded melanin-dots for cancer theranostics.

Copper(II) diethyldithiocarbamate complex (CuET), the metabolite of disulfiram complexed with copper, is the component responsible for cancer treatment efficacy of disulfiram. But the hydrophobic property of CuET limits its use in vivo, and an appropriate drug delivery system needs to be developed. Ultrasmall melanin nanoparticle (M-Dot) with excellent biosafety and biocompatibility properties has been synthesized in our previous studies. Herein we prepared CuET loaded with M-Dots through hydrophobic interaction, which could enhance the water solubility significantly. After the administration of M-Dots-CuET in mice tumor models, the nanoparticles showed good tumor accumulation as evidenced by the enhanced photoacoustic signal in tumor regions. M-Dots-CuET also displayed excellent tumor inhibition capability, and the tumor growth inhibition value (TGI) was 45.1%. When combined with photothermal therapy, the TGI reached up to 78.6%. In summary, M-Dots-CuET provide a new potential strategy for cancer theranostics.

Positive Patch Test Reactions to Carba Mix and Thiuram Mix: The North American Contact Dermatitis Group Experience (1994-2016).

BACKGROUND/OBJECTIVE: This study characterizes concomitant reactions to carba mix (CM) and thiuram mix (TM) in a large North American population. Because thiurams and dithiocarbamates have structural similarity, concomitant reactions are expected. METHODS: The 1994-2016 North American Contact Dermatitis Group data were analyzed. Patients with a final reaction interpreted as "allergic" to either CM or TM were included. RESULTS: A total of 49,758 patients were tested to both CM and TM. A total of 3437 (6.9%) had positive reactions to CM and/or TM including the following groups: CM+ only (n = 1403, 40.8%), TM+ only (n = 1068, 31.0%), or both (n = 966, 28.1%). A total of 47.5% of TM+ patients were positive to CM and 40.8% of CM+ patients were positive to TM. Male sex, occupationally related dermatitis, and hand involvement were significantly more common in individuals positive to CM and/or TM as compared with those who were negative (P < 0.0001). More than 80% of CM+/TM+ reactions were currently relevant. Gloves were the most common source of CM and TM; clothing and footwear were also frequent. CONCLUSIONS: Carba mix and TM remain important, clinically relevant allergens. Although significant concomitant reaction frequency was demonstrated, more than half of the patients reacting to either CM or TM would have been missed if both had not been tested, underscoring the importance of testing to both.

Biodegradable Quantum Composites for Synergistic Photothermal Therapy and Copper-Enhanced Chemotherapy.

In recent times, the combination therapy has garnered enormous interest owing to its great potential in clinical research. It has been reported that disulfiram, a clinical antialcoholism drug, could be degraded to diethyldithiocarbamate (DDTC) in vivo and subsequently result in the copper-DDTC complex (Cu(DDTC)2) toward ablating cancer cells. In addition, the ultrasmall copper sulfide nanodots (CuS NDs) have shown great potential in cancer treatment because of their excellent photothermal and photodynamic therapeutic efficiencies. Herein, by taking advantage of the interactions between CuS and DDTC, a new multifunctional nanoplatform based on DDTC-loaded CuS (CuS-DDTC) NDs is successfully fabricated, leading to the achievement of the synergistic effect of photothermal and copper enhanced chemotherapy. All experimental results verified promising synergistic therapeutic effects. Moreover, in vivo biocompatibility and metabolism experiments displayed that the CuS-DDTC NDs could be quickly excreted from the body with no apparent toxicity signs. Together, our findings indicated the superior synergistic therapeutic effect of photothermal and copper-enhanced chemotherapy, providing a promising anticancer strategy based on the CuS-DDTC NDs drug delivery system.

Transcriptional Induction of Cystathionine γ-Lyase, a Reactive Sulfur-Producing Enzyme, by Copper Diethyldithiocarbamate in Cultured Vascular Endothelial Cells.

As toxic substances can enter the circulating blood and cross endothelial monolayers to reach parenchymal cells in organs, vascular endothelial cells are an important target compartment for such substances. Reactive sulfur species protect cells against oxidative stress and toxic substances, including heavy metals. Reactive sulfur species are produced by enzymes, such as cystathionine γ-lyase (CSE), cystathionine ß-synthase, 3-mercaptopyruvate sulfurtransferase, and cysteinyl-tRNA synthetase. However, little is known about the regulatory mechanisms underlying the expression of these enzymes in vascular endothelial cells. Bio-organometallics is a research field that analyzes biological systems using organic-inorganic hybrid molecules (organometallic compounds and metal coordinating compounds) as molecular probes. In the present study, we analyzed intracellular signaling pathways that mediate the expression of reactive sulfur species-producing enzymes in cultured bovine aortic endothelial cells, using copper diethyldithiocarbamate (Cu10). Cu10 selectively upregulated CSE gene expression in vascular endothelial cells independent of cell density. This transcriptional induction of endothelial CSE required both the diethyldithiocarbamate scaffold and the coordinated copper ion. Additionally, the present study revealed that ERK1/2, p38 MAPK, and hypoxia-inducible factor (HIF)-1α/HIF-1ß pathways mediate transcriptional induction of endothelial CSE by Cu10. The transcription factors NF-κB, Sp1, and ATF4 were suggested to act in constitutive CSE expression, although the possibility that they are involved in the CSE induction by Cu10 cannot be excluded. The present study used a copper complex as a molecular probe to reveal that the transcription of CSE is regulated by multiple pathways in vascular endothelial cells, including ERK1/2, p38 MAPK, and HIF-1α/HIF-1ß. Bio-organometallics appears to be an effective strategy for analyzing the functions of intracellular signaling pathways in vascular endothelial cells.