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At least 379 records · Page 21

How much have adverse occupational health outcomes among construction workers improved over time? Evidence from 25 years of medical screening

Background Construction workers have always had a high risk of occupational illnesses. We used 25 years of data from a medical screening program serving older construction workers to determine how much health outcomes have improved over the past 60 years. Methods We investigated changes in relative risk for chest radiographs consistent with pneumoconiosis, COPD by spirometry, lung cancer mortality, and audiometry-assessed hearing impairment among workers participating in a medical screening program. Results were stratified by decade of first construction employment: before 1960, 1960–1969, 1970–1979, 1980–1989, and after 1990. Poisson and Cox regression analyses assessed relative risk by decade adjusted for age, sex, smoking, and years of construction trade work. Results Subjects were 94% male and, on average, 60 years old with 25 years of construction work. When compared to workers employed before 1960, those first employed after 1990 experienced the following reductions in model-adjusted relative risks: chronic obstructive pulmonary disease, 32%; all pneumoconiosis, 68%; parenchymal abnormalities, 35%; pleural abnormalities, 71%; hearing impairment, 20%; and lung cancer mortality, 48%. Risks started to decline in the 1960s with greatest reductions among workers first employed after 1970. Conclusions This study demonstrates the positive impact that adoption of occupational health protections have had over the past 60 years. The greatest risk reductions were observed for outcomes with strong regulatory and legal incentives to reduce exposures and associated risks, such as those associated with inhalation hazards (asbestos and silica), while lowest improvement was for hearing impairment, for which little regulatory enforcement and few prevention incentives have been adopted.

60 APPLIED LIFE SCIENCES↗

Risk of Pneumonitis and Outcomes After Mediastinal Proton Therapy for Relapsed/Refractory Lymphoma: A PTCOG and PCG Collaboration

Despite high response rates, there has been reluctance to use radiation therapy for patients with relapsed/refractory (r/r) Hodgkin (HL) or aggressive non-Hodgkin lymphoma (NHL) given concerns for subacute and late toxicities. Symptomatic pneumonitis, a subacute toxicity, has an incidence of 17% to 24% (≥grade 2) even with intensity modulated radiation therapy. Proton therapy (PT), which has no exit radiation dose, is associated with a lower dose to lung compared with other radiation techniques. As risk of radiation pneumonitis is associated with lung dose, we evaluated whether pneumonitis rates are lower with PT.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Normal Tissue Injury Induced by Photon and Proton Therapies: Gaps and Opportunities

Despite technological advances in radiation therapy (RT) and cancer treatment, patients still experience adverse effects. Proton therapy (PT) has emerged as a valuable RT modality that can improve treatment outcomes. Normal tissue injury is an important determinant of the outcome; therefore, for this review, we analyzed 2 databases: (1) clinical trials registered with ClinicalTrials.gov and (2) the literature on PT in PubMed, which shows a steady increase in the number of publications. Most studies in PT registered with ClinicalTrials.gov with results available are nonrandomized early phase studies with a relatively small number of patients enrolled. From the larger database of nonrandomized trials, we listed adverse events in specific organs/sites among patients with cancer who are treated with photons and protons to identify critical issues. The present data demonstrate dosimetric advantages of PT with favorable toxicity profiles and form the basis for comparative randomized prospective trials. A comparative analysis of 3 recently completed randomized trials for normal tissue toxicities suggests that for early stage non-small cell lung cancer, no meaningful comparison could be made between stereotactic body RT and stereotactic body PT due to low accrual (NCT01511081). In addition, for locally advanced non-small cell lung cancer, a comparison of intensity modulated RT with passive scattering PT (now largely replaced by spot-scanned intensity modulated PT), PT did not provide any benefit in normal tissue toxicity or locoregional failure over photon therapy. Finally, for locally advanced esophageal cancer, proton beam therapy provided a lower total toxicity burden but did not improve progression-free survival and quality of life (NCT01512589). The purpose of this review is to inform the limitations of current trials looking at protons and photons, considering that advances in technology, physics, and biology are a continuum, and to advocate for future trials geared toward accurate precision RT that need to be viewed as an iterative process in a defined path toward delivering optimal radiation treatment. A foundational understanding of the radiobiologic differences between protons and photons in tumor and normal tissue responses is fundamental to, and necessary for, determining the suitability of a given type of biologically optimized RT to a patient or cohort.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Automated bidirectional coupling of multiscale models of aerosol dosimetry: Validation with subject-specific deposition data

Assessing the toxicity of airborne particulate matter or the efficacy of inhaled drug depends upon accurate estimates of deposited fraction of inhaled materials. In silico approaches can provide important insights into site- or airway-specific deposition of inhaled aerosols in the respiratory system. In this study, we improved on our recently developed 3D/1D model that simulate aerosol transport and deposition in the whole lung over multiple breath cycles. A subject-specific multiscale lung model of a healthy male subject using computational fluid-particle dynamics (CFPD) in a 3D model of the oral cavity through the large bronchial airways entering each lobe was bidirectionally coupled with a recently improved Multiple Path Particle Dosimetry (MPPD) model to predict aerosol deposition over the entire respiratory tract over multiple breaths for four conditions matching experimental aerosol exposures in the same subject from which the model was developed. These include two particle sizes (1 and 2.9 μm) and two subject-specific breathing rates of ~300 ml/s (slow breathing) and ~750 ml/s (fast breathing) at a target tidal volume of 1 L. In silico predictions of retained fraction were 0.31 and 0.29 for 1 μm and 0.66 and 0.62 for 2.9 μm during slow and fast breathing, respectively, and compared well with experimental data (1 μm: 0.31 ± 0.01 (slow) and 0.27 ± 0.01 (fast), 2.9 μm: 0.63 ± 0.03 (slow) and 0.68 ± 0.02 (fast)). Furthermore, these results provide a great deal of confidence in the validity and reliability of our approach.

60 APPLIED LIFE SCIENCES↗

Chronic arsenic increases cell migration in BEAS-2B cells by increasing cell speed, cell persistence, and cell protrusion length

Highlights: • Chronic arsenic exposure primes lung epithelial cells for enhanced cell migration. • Chronic arsenic increases cell motility in an EGFR-dependent manner. • Chronic arsenic increases cell persistence in an EGFR-independent manner. • EGFR is sufficient, but not necessary for increasing cell protrusion length in chronic arsenic treated cells. There is a strong association between arsenic exposure and lung cancer development, however, the mechanism by which arsenic exposure leads to carcinogenesis is not clear. In our previous study, we observed that when BEAS-2B cells are chronically exposed to arsenic, there is an increase in secreted TGFα, as well as an increase in EGFR expression and activity. Further, these changes were broadly accompanied with an increase in cell migration. The overarching goal of this study was to acquire finer resolution of the arsenic-dependent changes in cell migration, as well as to understand the role of increased EGFR expression and activity levels in the underlying mechanisms of cell migration. To do this, we used a combination of biochemical and single cell assays, and observed chronic arsenic treatment enhancing cell migration by increasing cell speed, cell persistence and cell protrusion length. All three parameters were further increased by the addition of TGFα, indicating EGFR activity is sufficient to enhance those aspects of cell migration. In contrast, EGFR activity was necessary for the increase in cell speed, as it was reversed with an EGFR inhibitor, AG1478, but was not necessary to enhance persistence and protrusion length. From these data, we were able to isolate both EGFR-dependent and –independent features of cell migration that were enhanced by chronic arsenic exposure.

60 APPLIED LIFE SCIENCES↗

Ultrastructural Location and Interactions of the Immunoglobulin Receptor Binding Sequence within Fibrillar Type I Collagen

Collagen type I is a major constituent of animal bodies. It is found in large quantities in tendon, bone, skin, cartilage, blood vessels, bronchi, and the lung interstitium. It is also produced and accumulates in large amounts in response to certain inflammations such as lung fibrosis. Our understanding of the molecular organization of fibrillar collagen and cellular interaction motifs, such as those involved with immune-associated molecules, continues to be refined. In this study, antibodies raised against type I collagen were used to label intact D-periodic type I collagen fibrils and observed with atomic force microscopy (AFM), and X-ray diffraction (XRD) and immunolabeling positions were observed with both methods. The antibodies bind close to the C-terminal telopeptide which verifies the location and accessibility of both the major histocompatibility complex (MHC) class I (MHCI) binding domain and C-terminal telopeptide on the outside of the collagen fibril. The close proximity of the C-telopeptide and the MHC1 domain of type I collagen to fibronectin, discoidin domain receptor (DDR), and collagenase cleavage domains likely facilitate the interaction of ligands and receptors related to cellular immunity and the collagen-based Extracellular Matrix.

59 BASIC BIOLOGICAL SCIENCES↗

Transfer function analysis of the autonomic response to respiratory activity during random interval breathing

We report a new method for the noninvasive characterization of the frequency response of the autonomic nervous system (ANS) in mediating fluctuations in heart rate (HR). The approach entails computation of the transfer function magnitude and phase between instantaneous lung volume and HR. Broad band fluctuations in lung volume were initiated when subjects breathed on cue to a sequence of beeps spaced randomly in time. We studied 10 subjects in both supine and standing positions. The transfer function, averaged among all the subjects, showed systematic differences between the two postures, reflecting the differing frequency responses of the sympathetic and parasympathetic divisions of the ANS.

Non-NASA Center↗

Pulmonary function in space

The lung is exquisitely sensitive to gravity, and so it is of interest to know how its function is altered in the weightlessness of space. Studies on National Aeronautics and Space Administration (NASA) Spacelabs during the last 4 years have provided the first comprehensive data on the extensive changes in pulmonary function that occur in sustained microgravity. Measurements of pulmonary function were made on astronauts during space shuttle flights lasting 9 and 14 days and were compared with extensive ground-based measurements before and after the flights. Compared with preflight measurements, cardiac output increased by 18% during space flight, and stroke volume increased by 46%. Paradoxically, the increase in stroke volume occurred in the face of reductions in central venous pressure and circulating blood volume. Diffusing capacity increased by 28%, and the increase in the diffusing capacity of the alveolar membrane was unexpectedly large based on findings in normal gravity. The change in the alveolar membrane may reflect the effects of uniform filling of the pulmonary capillary bed. Distributions of blood flow and ventilation throughout the lung were more uniform in space, but some unevenness remained, indicating the importance of nongravitational factors. A surprising finding was that airway closing volume was approximately the same in microgravity and in normal gravity, emphasizing the importance of mechanical properties of the airways in determining whether they close. Residual volume was unexpectedly reduced by 18% in microgravity, possibly because of uniform alveolar expansion. The findings indicate that pulmonary function is greatly altered in microgravity, but none of the changes observed so far will apparently limit long-term space flight. In addition, the data help to clarify how gravity affects pulmonary function in the normal gravity environment on Earth.

short duration↗

A dual-input nonlinear system analysis of autonomic modulation of heart rate

Linear analyses of fluctuations in heart rate and other hemodynamic variables have been used to elucidate cardiovascular regulatory mechanisms. The role of nonlinear contributions to fluctuations in hemodynamic variables has not been fully explored. This paper presents a nonlinear system analysis of the effect of fluctuations in instantaneous lung volume (ILV) and arterial blood pressure (ABP) on heart rate (HR) fluctuations. To successfully employ a nonlinear analysis based on the Laguerre expansion technique (LET), we introduce an efficient procedure for broadening the spectral content of the ILV and ABP inputs to the model by adding white noise. Results from computer simulations demonstrate the effectiveness of broadening the spectral band of input signals to obtain consistent and stable kernel estimates with the use of the LET. Without broadening the band of the ILV and ABP inputs, the LET did not provide stable kernel estimates. Moreover, we extend the LET to the case of multiple inputs in order to accommodate the analysis of the combined effect of ILV and ABP effect on heart rate. Analyzes of data based on the second-order Volterra-Wiener model reveal an important contribution of the second-order kernels to the description of the effect of lung volume and arterial blood pressure on heart rate. Furthermore, physiological effects of the autonomic blocking agents propranolol and atropine on changes in the first- and second-order kernels are also discussed.

NASA Discipline Regulatory Physiology↗

Cisplatin-Induced Alteration on Membrane Composition of A549 Cells Revealed by ToF-SIMS

Cisplatin has been clinically used for treatment of solid tumors such as non-small-cell lung cancer for decades. However, tumor resistance may be acquired with losing the antitumor activity of cisplatin. As cellular membrane is the first barrier that cisplatin has to overcome before its further action inside the cells, the membrane composition must play a vital role in the cisplatin uptake and excretion which further influences cisplatin sensitivity. In this work, we applied ToF-SIMS surface analysis combined with principle component analysis to distinguish the differences of cell membrane composition between non-small-cell lung cancer cells (A549) and its cisplatin resistant counterpart A549/DDP cells. The decreased phosphatidylcholine content and more abundant cholesterol were observed in the drug resistant cell surfaces, indicating the decreased membrane fluidity of A549/DDP cells. Moreover, we further compared membrane composition of A549 and A549/DDP cells after being treated with different concentrations of cisplatin. A higher composition level of proteins was discovered on all groups of A549/DDP cell membranes. The altered surface chemistry of cellular membranes induced by cisplatin indicate the significance of membrane structures in the drug resistance, which deserves further investigations to this regard.

Zhang, Yanyan↗

Cohort-based pan-cancer analysis and experimental studies reveal ISG15 gene as a novel biomarker for prognosis and immunotherapy efficacy prediction

Abstract ISG15, an interferon-stimulated ubiquitin-like protein, plays a multifaceted role in tumorigenesis and immune regulation. This study comprehensively evaluates ISG15 as a prognostic biomarker and predictor of immunotherapy response through pan-cancer bioinformatics analysis and experimental validation. By integrating multiomics data from TCGA, GEO, and clinical cohorts, we found that ISG15 is significantly overexpressed in multiple cancers and generally correlates with poor prognosis. Elevated ISG15 expression is associated with increased immune checkpoint gene expression, particularly PD-L1, and immune infiltration, notably M2-like tumor-associated macrophages. Immunohistochemistry and multiplexed immunofluorescence confirmed a strong positive correlation between ISG15, PD-L1, and M2-TAM infiltration in lung and gastric cancer samples. Functional analysis at the single-cell level revealed significant associations between ISG15 and tumor proliferation, angiogenesis, and immune suppression. Immunotherapy cohort analysis demonstrated that tumors with high ISG15 expression responded favorably to PD-L1 inhibitors but exhibited resistance to CTLA-4 blockade, findings further validated in lung cancer patients receiving anti-PD-1 therapy. These results suggest that ISG15 is a promising biomarker for prognosis and immunotherapy response prediction across cancers. Its integration into clinical decision-making may enhance personalized treatment strategies, improve immunotherapy outcomes, and provide new insights into the tumor immune microenvironment, cancer progression, and potential therapeutic targets for future drug development.

Immunology↗

ProZES: the methodology and software tool for assessment of assigned share of radiation in probability of cancer occurrence

ProZES is a software tool for estimating the probability that a given cancer was caused by preceding exposure to ionising radiation. ProZES calculates this probability, the assigned share, for solid cancers and hematopoietic malignant diseases, in cases of exposures to low-LET radiation, and for lung cancer in cases of exposure to radon. User-specified inputs include birth year, sex, type of diagnosed cancer, age at diagnosis, radiation exposure history and characteristics, and smoking behaviour for lung cancer. Cancer risk models are an essential part of ProZES. Linking disease and exposure to radiation involves several methodological aspects, and assessment of uncertainties received particular attention. ProZES systematically uses the principle of multi-model inference. Models of radiation risk were either newly developed or critically re-evaluated for ProZES, including dedicated models for frequent types of cancer and, for less common diseases, models for groups of functionally similar cancer sites. The low-LET models originate mostly from the study of atomic bomb survivors in Hiroshima and Nagasaki. Risks predicted by these models are adjusted to be applicable to the population of Germany and to different time periods. Adjustment factors for low dose rates and for a reduced risk during the minimum latency time between exposure and cancer are also applied. The development of the methodology and software was initiated and supported by the German Federal Ministry for the Environment, Nature Conservation and Nuclear Safety (BMU) taking up advice by the German Commission on Radiological Protection (SSK, Strahlenschutzkommission). These provide the scientific basis to support decision making on compensation claims regarding malignancies following occupational exposure to radiation in Germany.

97 MATHEMATICS AND COMPUTING↗

A susceptibility gene signature for ERBB2-driven mammary tumour development and metastasis in collaborative cross mice

Background: Deeper insights into ERBB2-driven cancers are essential to develop new treatment approaches for ERBB2+ breast cancers (BCs). We employed the Collaborative Cross (CC) mouse model to unearth genetic factors underpinning Erbb2-driven mammary tumour development and metastasis. Methods: 732 F1 hybrid female mice between FVB/N MMTV-Erbb2 and 30 CC strains were monitored for mammary tumour phenotypes. GWAS pinpointed SNPs that influence various tumour phenotypes. Multivariate analyses and models were used to construct the polygenic score and to develop a mouse tumour susceptibility gene signature (mTSGS), where the corresponding human ortholog was identified and designated as hTSGS. The importance and clinical value of hTSGS in human BC was evaluated using public datasets, encompassing TCGA, METABRIC, GSE96058, and I-SPY2 cohorts. The predictive power of mTSGS for response to chemotherapy was validated in vivo using genetically diverse MMTV-Erbb2 mice. Findings: Distinct variances in tumour onset, multiplicity, and metastatic patterns were observed in F1-hybrid female mice between FVB/N MMTV-Erbb2 and 30 CC strains. Besides lung metastasis, liver and kidney metastases emerged in specific CC strains. GWAS identified specific SNPs significantly associated with tumour onset, multiplicity, lung metastasis, and liver metastasis. Multivariate analyses flagged SNPs in 20 genes (Stx6, Ramp1, Traf3ip1, Nckap5, Pfkfb2, Trmt1l, Rprd1b, Rer1, Sepsecs, Rhobtb1, Tsen15, Abcc3, Arid5b, Tnr, Dock2, Tti1, Fam81a, Oxr1, Plxna2, and Tbc1d31) independently tied to various tumour characteristics, designated as a mTSGS. hTSGS scores (hTSGSS) based on their transcriptional level showed prognostic values, superseding clinical factors and PAM50 subtype across multiple human BC cohorts, and predicted pathological complete response independent of and superior to MammaPrint score in I-SPY2 study. The power of mTSGS score for predicting chemotherapy response was further validated in an in vivo mouse MMTV-Erbb2 model, showing that, like findings in human patients, mouse tumours with low mTSGS scores were most likely to respond to treatment. Interpretation: Our investigation has unveiled many new genes predisposing individuals to ERBB2-driven cancer. Translational findings indicate that hTSGS holds promise as a biomarker for refining treatment strategies for patients with BC.

60 APPLIED LIFE SCIENCES↗

Size dependent infectivity of SARS-CoV-2 via respiratory droplets spread through central ventilation systems

In this work, we evaluate the transport of respiratory droplets that carry SARS-CoV-2 through central air handling systems in multiroom buildings. Respiratory droplet size modes arise from the bronchioles representing the lungs and lower respiratory tract, the larynx representing the upper respiratory tract including vocal cords, or the oral cavity. The size distribution of each mode remains largely conserved, although the magnitude of each droplet mode changes as infected individuals breathe, speak, sing, laugh, cough, and sneeze. Here we evaluate how each type of respiratory droplet transits through central ventilation systems and the implications thereof for infectivity of COVID-19. We find that while larger oral droplets can transmit through the air handling systems, their size and concentration are greatly reduced with but few oral droplets leaving the source room. In contrast, the smaller droplets that originate from the bronchioles and larynx are much more effective in transiting through the air handling system into connected rooms. This suggests that the ratio of lower respiratory or deep lung infections may increase relative to upper respiratory infections in rooms connected by central air handling systems. Also, increasing the temperature and humidity in the range considered after the droplets have achieved an “equilibrium” size reduces the probability of infection.

60 APPLIED LIFE SCIENCES↗

Particle emissions from mobile sources: Discussion of ultrafine particle emissions and definition

There is no universally agreed upon definition for ultrafine particles (UFP). Commonly used definitions for UFP are either particle number below 100 nm or total particle number, but without an agreed upon lower cut point. For example, a lower cut point of 3 nm compared to 10 nm could result in a substantially higher count. Another definition for UFP is total particle mass but without a commonly agreed upon aerodynamic diameter upper cut point, e.g., below 100 nm, 200 nm, 300 nm, etc. Yet another definition is lung deposited surface area weighted by lung deposition fraction, found mainly in the particle mobility diameter range from 20 to 400 nm. It is clear from these definitions that there are inconsistencies in the way UFP is used and defined in the literature. Sometimes these metrics are well correlated, sometimes not. In this paper we suggest three exposure metrics: UFP-N, UFP-M, and UFP-S, that we believe will add clarity. These metrics represent total number, mass, and surface area below 500 nm, respectively. For surface area and mass, the 500 nm cut point can be either aerodynamic or mobility diameter depending upon measurement methodology. For all metrics, this cut point captures nearly all of the primary particle emissions from mobile sources. Furthermore, UFP-N would include a lower cut point of 3–6 nm and would not require an upper size cut point because there is very little particle number above 500 nm or even above 100 nm. Thus, our definition of UFP-N is consistent with the current definition of ultrafine number except for, importantly, the specification of a lower cut point. These exposure metrics can help facilitate consistency in the characterization of both short- and long-term UFP ambient exposures and associated health effects in epidemiological studies.

42 ENGINEERING↗

Subject-specific multi-scale modeling of the fate of inhaled aerosols

Determining the fate of inhaled aerosols in the respiratory system is essential in assessing the potential toxicity of inhaled airborne materials, responses to airborne pathogens, or in improving inhaled drug delivery. The availability of high-resolution clinical lung imaging and advances in the reconstruction of lung airways from CT images have led to the development of subject-specific in-silico 3D models of aerosol dosimetry, often referred to as computational fluid-particle-dynamics (CFPD) models. As CFPD models require extensive computing resources, they are typically confined to the upper and large airways. These models can be combined with lower-dimensional models to form multiscale models that predict the transport and deposition of inhaled aerosols in the entire respiratory tract. Understanding where aerosols deposit is only the first of potentially several key events necessary to predict an outcome, being a detrimental health effect or a therapeutic response. To that end, multiscale approaches that combine CFPD with physiologically-based pharmacokinetics (PBPK) models have been developed to evaluate the absorption, distribution, metabolism, and excretion (ADME) of toxic or medicinal chemicals in one or more compartments of the human body. CFPD models can also be combined with host cell dynamics (HCD) models to assess regional immune system responses. Here, this paper reviews the state of the art of these different multiscale approaches and discusses the potential role of personalized or subject-specific modeling in respiratory health.

60 APPLIED LIFE SCIENCES↗

Physical structure of constitutional isomers influences antiproliferation activity of thiosemicarbazone-alkylthiocarbamate copper complexes

A series of hybrid thiosemicarbazone-alkylthiocarbamate copper complexes with similar electronic environments but distinct physical structures have been prepared, characterized, and evaluated for antiproliferation activity. The complexes include the constitutional isomers (1-phenylpropane-1-imine-(O-ethylthiocarbamato)-2-one-(N-methylthiosemicarbazonato))copper(II) (CuL 1 ) and (1-phenylpropane-1-one-(N-methylthiosemicarbazonato)-2-imine-(O-ethylthiocarbamato))copper(II) (CuL 2 ) along with (1-propane-1-imine-(O-ethylthiocarbamato)-2-one-(N-methylthiosemicarbazonato))copper(II) (CuL 3 ). Complexes CuL 1 and CuL 2 differ in the positions of the pendent thiosemicarbazone (TSC) and alkylthiocarbamate (ATC) moieties on the 1-phenylpropane backbone. Complex CuL 3 employs a propane backbone with the TSC in the 2-position as in CuL 1 . The isomer pair CuL 1 and CuL 2 have equivalent electronic environments with indistinguishable Cu II/I potentials (E 1/2 = -0.86 V vs. ferrocenium/ferrocene) and electron paramagnetic resonance (EPR) spectra (g ∥ = 2.26, g ⊥ = 2.08). The electronic structure of CuL 3 has a similar E 1/2 of -0.84 V and identical EPR parameters to CuL 1, 2 . Single crystal X-ray diffraction studies confirm a consistent donor environment with no substantial variation in the Cusingle bondN or Cusingle bondS bond distances and angles between the complexes. The antiproliferation activities of the CuL 1–3 were evaluated against the lung adenocarcinoma cell line (A549) and nonmalignant lung fibroblast cell line (IMR-90) using the MTT assay. CuL 1 had the highest A549 activity ( A549 EC 50 = 0.065 μM) and selectivity ( IMR-90 EC 50 / A549 EC 50 = 20). The constitutional isomer CuL 2 displayed decreased A549 activity (0.18 μM) and selectivity (10.6). The complex CuL 3 displayed activity (0.009 μM) similar to CuL 1 but with a lack of selectivity (1.0). Cellular copper loading determined by ICP-MS was consistent with the activity and selectivity trends. The complexes CuL 1–3 did not induce reactive oxygen species (ROS) generation.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Synthesis, Characterization, and Biological Activity of Hybrid Thiosemicarbazone–Alkylthiocarbamate Metal Complexes

A series of hybrid ligands (H 2 L 1 –H 2 L 3 ) derived from 4-methyl-3-thiosemicarbazide and hydrazinecarbothioic acid O-alkyl esters were synthesized and characterized by NMR. The ligands were chelated with copper (4–6), nickel (7–9), and zinc (10–12) and characterized by spectroscopy, electrochemistry, and single crystal X-ray crystallography. The chelated metals displayed substantial anodic shifts in the Cu II/I reduction potential of ~160 mV relative to their bis(thiosemicarbazone) analogues. The metal chelates 4–12 were evaluated for potential anticancer activity by MTT assays, and selected results were confirmed by clonogenic and trypan blue assays. The copper derivatives 4 and 6 were found to have potent and cancer-selective antiproliferative effects, with GI 50 values less than 100 nM in A549 lung adenocarcinoma cells compared with at least 20-fold less activity in IMR90 nonmalignant lung fibroblasts. In comparison, the nickel complexes were much less active and had little cancer-selectivity. Varying by ligand, the zinc complexes were less potent or had comparable activity compared to that of the corresponding copper complex. UV–visible spectroscopy indicated that zinc complex 10 was transmetalated in the presence of equimolar copper, whereas nickel complex 7 was not. Copper complexes 4 and 6 were also assessed in the NCI60 screen and were found to have cytotoxic activity against most solid tumor cell lines. In MTT assays, 4 and 6 were substantially more active against A549 cancer cells than Cu(ATSM) and were more cancer-selective (for A549 compared to IMR-90) than Cu(GTSM). Finally, our results suggest that hybrid thiosemicarbazone–alkylthiocarbamate copper complexes have potential for development as new anticancer agents.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗