A nested case-control study of untargeted albumin adductomics and acute myeloid leukemia.

Environmental exposures often produce reactive electrophiles in vivo, leading to oxidative stress, which plays a major role in carcinogenesis. These electrophiles frequently form adducts with human albumin, which can be measured to assess in vivo oxidative stress. Here, we aimed to examine the associations between circulatory albumin adducts and acute myeloid leukemia (AML), the most common adult myeloid leukemia that showed consistent associations with environmental exposures. We conducted a nested case-control study of 52 incident AML cases and 103 controls matched on age, sex and race within two prospective cohorts: the CLUE and PLCO studies. We measured 42 untargeted albumin adducts in prediagnostic samples using liquid chromatography-high-resolution mass spectrometry. Circulatory albumin adducts were associated with AML in conditional logistic regression models. For instance, higher levels of Cys34 disulfide adduct of the S-γ-glutamylcysteine, a precursor of the essential antioxidant, glutathione were associated with a lower risk of AML (odds ratios [95% confidence intervals]) for the 1st, 2nd and 3rd tertiles were 1.0, 0.65 (0.31-1.36) and 0.31 (0.12-0.80), respectively (P-trend = .01). These associations were largely driven by effects present among cases diagnosed at or above the median follow-up time of 5.5 years. In conclusion, applying a novel approach to characterize exposures in the prediagnostic samples, we found evidence supporting the notion that oxidative stress may play a role in the pathogenesis of AML. Our findings offer insight into AML etiology and may be relevant in identifying novel therapeutic targets.

Metabolome-wide association study of occupational exposure to benzene.

Benzene is a recognized hematotoxin and leukemogen; however, its mechanism of action in humans remain unclear. To provide insight into the processes underlying benzene hematotoxicity, we performed high-resolution metabolomic profiling of plasma collected from a cross-sectional study of 33 healthy workers exposed to benzene (median 8-h time-weighted average exposure; 20 ppma), and 25 unexposed controls in Shanghai, China. Metabolic features associated with benzene were identified using a metabolome-wide association study (MWAS) that tested for the relationship between feature intensity and benzene exposure. MWAS identified 478 mass spectral features associated with benzene exposure at false discovery rate < 20%. Comparison to a list of 13 known benzene metabolites and metabolites predicted using a multi-component biotransformation algorithm showed five metabolites were detected, which included the known metabolites phenol and benzene diolepoxide. Metabolic pathway enrichment identified 41 pathways associated with benzene exposure, with altered pathways including carnitine shuttle, fatty acid metabolism, sulfur amino acid metabolism, glycolysis, gluconeogenesis and branched chain amino acid metabolism. These results suggest disruption to fatty acid uptake, energy metabolism and increased oxidative stress, and point towards pathways related to mitochondrial dysfunction, which has previously been linked to benzene exposure in animal models and human studies. Taken together, these results suggest benzene exposure is associated with disruption of mitochondrial pathways, and provide promising, systems biology biomarkers for risk assessment of benzene-induced hematotoxicity in humans.

Extending the HSA-Cys34-Adductomics Pipeline to Modifications at Lys525.

We previously developed an adductomics pipeline that employed nanoflow liquid chromatography and high-resolution tandem mass spectrometry (nLC-HR-MS/MS) plus informatics to perform an untargeted detection of modifications to Cys34 in the tryptic T3 peptide of human serum albumin (HSA) (21ALVLIAFAQYLQQC34PFEDHVK41). In order to detect these peptide modifications without targeting specific masses, the pipeline interrogates MS2 ions that are signatures of the T3 peptide. The pipeline had been pilot-tested with archived plasma from healthy human subjects, and several of the 43 Cys34 adducts were highly associated with the smoking status. In the current investigation, we adapted the pipeline to include modifications to the ε-amino group of Lys525─a major glycation site in HSA─and thereby extend the coverage to products of Schiff bases that cannot be produced at Cys34. Because trypsin is generally unable to digest proteins at modified lysines, our pipeline detects miscleaved tryptic peptides with the sequence 525KQTALVELVK534. Adducts of both Lys525 and Cys34 are measured in a single nLC-HR-MS/MS run by increasing the mass range of precursor ions in MS1 scans and including both triply and doubly charged precursor ions for collision-induced dissociation fragmentation. For proof of principle, we applied the Cys34/Lys525 pipeline to archived plasma specimens from a subset of the same volunteer subjects used in the original investigation. Twelve modified Lys525 peptides were detected, including products of glycation (fructosyl-lysine plus advanced-glycated-end products), acetylation, and elimination of ammonia and water. Surprisingly, the carbamylated and glycated adducts were present at significantly lower levels in smoking subjects. By including a larger class of in vivo nucleophilic substitution reactions, the Cys34/Lys525 adductomics pipeline expands exposomic investigations of unknown human exposure to reactive electrophiles derived from both exogenous and endogenous sources.

Agnostic Cys34-albumin adductomics and DNA methylation: Implication of N-acetylcysteine in lung carcinogenesis years before diagnosis.

Although smoking and oxidative stress are known contributors to lung carcinogenesis, their mechanisms of action remain poorly understood. To shed light into these mechanisms, we applied a novel approach using Cys34-adductomics in a lung cancer nested case-control study (n = 212). Adductomics profiles were integrated with DNA-methylation data at established smoking-related CpG sites measured in the same individuals. Our analysis identified 42 Cys34-albumin adducts, of which 2 were significantly differentially abundant in cases and controls: adduct of N-acetylcysteine (NAC, p = 4.15 × 10-3 ) and of cysteinyl-glycine (p = 7.89 × 10-3 ). Blood levels of the former were found associated to the methylation levels at 11 smoking-related CpG sites. We detect, for the first time in prospective blood samples, and irrespective of time to diagnosis, decreased levels of NAC adduct in lung cancer cases. Altogether, our results highlight the potential role of these adducts in the oxidative stress response contributing to lung carcinogenesis years before diagnosis.

SimExTargId: a comprehensive package for real-time LC-MS data acquisition and analysis.

Summary: Liquid chromatography mass spectrometry (LC-MS) is the favored method for untargeted metabolomic analysis of small molecules in biofluids. Here we present SimExTargId, an open-source R package for autonomous analysis of metabolomic data and real-time observation of experimental runs. This simultaneous, fully automated and multi-threaded (optional) package is a wrapper for vendor-independent format conversion (ProteoWizard), xcms- and CAMERA- based peak-picking, MetMSLine-based pre-processing and covariate-based statistical analysis. Users are notified of detrimental instrument drift or errors by email. Also included are two shiny applications, targetId for real-time MS2 target identification, and peakMonitor to monitor targeted metabolites. Availability and implementation: SimExTargId is publicly available under GNU LGPL v3.0 license at https://github.com/JosieLHayes/simExTargId, which includes a vignette with example data. SimExTargId should be installed on a dedicated data-processing workstation or server that is networked to the LC-MS platform to facilitate MS1 profiling of metabolomic data. Supplementary information: Supplementary data are available at Bioinformatics online.

Adductomic signatures of benzene exposure provide insights into cancer induction.

Although benzene has long been recognized as a cause of human leukemia, the mechanism by which this simple molecule causes cancer has been problematic. A complicating factor is benzene metabolism, which produces many reactive intermediates, some specific to benzene and others derived from redox processes. Using archived serum from 20 nonsmoking Chinese workers, 10 with and 10 without occupational exposure to benzene (exposed: 3.2-88.9 ppm, controls: 0.002-0.020 ppm), we employed an adductomic pipeline to characterize protein modifications at Cys34 of human serum albumin, a nucleophilic hotspot in extracellular fluids. Of the 47 measured human serum albumin modifications, 39 were present at higher concentrations in benzene-exposed workers than in controls and many of the exposed-control differences were statistically significant. Correlation analysis identified three prominent clusters of adducts, namely putative modifications by benzene oxide and a benzene diolepoxide that grouped with other measures of benzene exposure, adducts of reactive oxygen and carbonyl species, and Cys34 disulfides of small thiols that are formed following oxidation of Cys34. Benzene diolepoxides are potent mutagens and carcinogens that have received little attention as potential causes of human leukemia. Reactive oxygen and carbonyl species-generated by redox processes involving polyphenolic benzene metabolites and by Cyp2E1 regulation following benzene exposure-can modify DNA and proteins in ways that contribute to cancer. The fact that these diverse human serum albumin modifications differed between benzene-exposed and control workers suggests that benzene can increase leukemia risks via multiple pathways involving a constellation of reactive molecules.

Untargeted lipidomic features associated with colorectal cancer in a prospective cohort.

BACKGROUND: Epidemiologists are beginning to employ metabolomics and lipidomics with archived blood from incident cases and controls to discover causes of cancer. Although several such studies have focused on colorectal cancer (CRC), they all followed targeted or semi-targeted designs that limited their ability to find discriminating molecules and pathways related to the causes of CRC. METHODS: Using an untargeted design, we measured lipophilic metabolites in prediagnostic serum from 66 CRC patients and 66 matched controls from the European Prospective Investigation into Cancer and Nutrition (Turin, Italy). Samples were analyzed by liquid chromatography-high-resolution mass spectrometry (LC-MS), resulting in 8690 features for statistical analysis. RESULTS: Rather than the usual multiple-hypothesis-testing approach, we based variable selection on an ensemble of regression methods, which found nine features to be associated with case-control status. We then regressed each selected feature on time-to-diagnosis to determine whether the feature was likely to be either a potentially causal biomarker or a reactive product of disease progression (reverse causality). CONCLUSIONS: Of the nine selected LC-MS features, four appear to be involved in CRC etiology and merit further investigation in prospective studies of CRC. Four other features appear to be related to progression of the disease (reverse causality), and may represent biomarkers of value for early detection of CRC.

Monte Carlo methods for nonparametric regression with heteroscedastic measurement error.

Nonparametric regression is a fundamental problem in statistics but challenging when the independent variable is measured with error. Among the first approaches was an extension of deconvoluting kernel density estimators for homescedastic measurement error. The main contribution of this article is to propose a new simulation-based nonparametric regression estimator for the heteroscedastic measurement error case. Similar to some earlier proposals, our estimator is built on principles underlying deconvoluting kernel density estimators. However, the proposed estimation procedure uses Monte Carlo methods for estimating nonlinear functions of a normal mean, which is different than any previous estimator. We show that the estimator has desirable operating characteristics in both large and small samples and apply the method to a study of benzene exposure in Chinese factory workers.

Cys34 Adductomes Differ between Patients with Chronic Lung or Heart Disease and Healthy Controls in Central London.

Oxidative stress generates reactive species that modify proteins, deplete antioxidant defenses, and contribute to chronic obstructive pulmonary disease (COPD) and ischemic heart disease (IHD). To determine whether protein modifications differ between COPD or IHD patients and healthy subjects, we performed untargeted analysis of adducts at the Cys34 locus of human serum albumin (HSA). Biospecimens were obtained from nonsmoking participants from London, U.K., including healthy subjects (n = 20) and patients with COPD (n = 20) or IHD (n = 10). Serum samples were digested with trypsin and analyzed by liquid chromatography-high resolution mass spectrometry. Effects of air pollution on adduct levels were also investigated based on estimated residential exposures to PM2.5, O3 and NO2. For the 39 adducts with sufficient data, levels were essentially identical in blood samples collected from the same subjects on two consecutive days, consistent with the 28 day residence time of HSA. Multivariate linear regression revealed 21 significant associations, mainly with the underlying diseases but also with air-pollution exposures (p-value < 0.05). Interestingly, most of the associations indicated that adduct levels decreased with the presence of disease or increased pollutant concentrations. Negative associations of COPD and IHD with the Cys34 disulfide of glutathione and two Cys34 sulfoxidations, were consistent with previous results from smoking and nonsmoking volunteers and nonsmoking women exposed to indoor combustion of coal and wood.

compMS2Miner: An Automatable Metabolite Identification, Visualization, and Data-Sharing R Package for High-Resolution LC-MS Data Sets.

A long-standing challenge of untargeted metabolomic profiling by ultrahigh-performance liquid chromatography-high-resolution mass spectrometry (UHPLC-HRMS) is efficient transition from unknown mass spectral features to confident metabolite annotations. The compMS2Miner (Comprehensive MS2 Miner) package was developed in the R language to facilitate rapid, comprehensive feature annotation using a peak-picker-output and MS2 data files as inputs. The number of MS2 spectra that can be collected during a metabolomic profiling experiment far outweigh the amount of time required for pain-staking manual interpretation; therefore, a degree of software workflow autonomy is required for broad-scale metabolite annotation. CompMS2Miner integrates many useful tools in a single workflow for metabolite annotation and also provides a means to overview the MS2 data with a Web application GUI compMS2Explorer (Comprehensive MS2 Explorer) that also facilitates data-sharing and transparency. The automatable compMS2Miner workflow consists of the following steps: (i) matching unknown MS1 features to precursor MS2 scans, (ii) filtration of spectral noise (dynamic noise filter), (iii) generation of composite mass spectra by multiple similar spectrum signal summation and redundant/contaminant spectra removal, (iv) interpretation of possible fragment ion substructure using an internal database, (v) annotation of unknowns with chemical and spectral databases with prediction of mammalian biotransformation metabolites, wrapper functions for in silico fragmentation software, nearest neighbor chemical similarity scoring, random forest based retention time prediction, text-mining based false positive removal/true positive ranking, chemical taxonomic prediction and differential evolution based global annotation score optimization, and (vi) network graph visualizations, data curation, and sharing are made possible via the compMS2Explorer application. Metabolite identities and comments can also be recorded using an interactive table within compMS2Explorer. The utility of the package is illustrated with a data set of blood serum samples from 7 diet induced obese (DIO) and 7 nonobese (NO) C57BL/6J mice, which were also treated with an antibiotic (streptomycin) to knockdown the gut microbiota. The results of fully autonomous and objective usage of compMS2Miner are presented here. All automatically annotated spectra output by the workflow are provided in the Supporting Information and can alternatively be explored as publically available compMS2Explorer applications for both positive and negative modes ( https://wmbedmands.shinyapps.io/compMS2_mouseSera_POS and https://wmbedmands.shinyapps.io/compMS2_mouseSera_NEG ). The workflow provided rapid annotation of a diversity of endogenous and gut microbially derived metabolites affected by both diet and antibiotic treatment, which conformed to previously published reports. Composite spectra (n = 173) were autonomously matched to entries of the Massbank of North America (MoNA) spectral repository. These experimental and virtual (lipidBlast) spectra corresponded to 29 common endogenous compound classes (e.g., 51 lysophosphatidylcholines spectra) and were then used to calculate the ranking capability of 7 individual scoring metrics. It was found that an average of the 7 individual scoring metrics provided the most effective weighted average ranking ability of 3 for the MoNA matched spectra in spite of potential risk of false positive annotations emerging from automation. Minor structural differences such as relative carbon-carbon double bond positions were found in several cases to affect the correct rank of the MoNA annotated metabolite. The latest release and an example workflow is available in the package vignette ( https://github.com/WMBEdmands/compMS2Miner ) and a version of the published application is available on the shinyapps.io site ( https://wmbedmands.shinyapps.io/compMS2Example ).

Profiling the Serum Albumin Cys34 Adductome of Solid Fuel Users in Xuanwei and Fuyuan, China.

Xuanwei and Fuyuan counties in China have the highest lung cancer rates in the world due to household air pollution from combustion of smoky coal for cooking and heating. To discover potential biomarkers of indoor combustion products, we profiled adducts at the Cys34 locus of human serum albumin (HSA) in 29 nonsmoking Xuanwei and Fuyuan females who used smoky coal, smokeless coal, or wood and 10 local controls who used electricity or gas fuel. Our untargeted "adductomics" method detected 50 tryptic peptides of HSA, containing Cys34 and prominent post-translational modifications. Putative adducts included Cys34 oxidation products, mixed disulfides, rearrangements, and truncations. The most significant differences in adduct levels across fuel types were observed for S-glutathione (S-GSH) and S-γ-glutamylcysteine (S-γ-GluCys), both of which were present at lower levels in subjects exposed to combustion products than in controls. After adjustment for age and personal measurements of airborne benzo(a)pyrene, the largest reductions in levels of S-GSH and S-γ-GluCys relative to controls were observed for users of smoky coal, compared to users of smokeless coal and wood. These results point to possible depletion of GSH, an essential antioxidant, and its precursor γ-GluCys in nonsmoking females exposed to indoor-combustion products in Xuanwei and Fuyuan, China.

T3DB: the toxic exposome database.

The exposome is defined as the totality of all human environmental exposures from conception to death. It is often regarded as the complement to the genome, with the interaction between the exposome and the genome ultimately determining one's phenotype. The 'toxic exposome' is the complete collection of chronically or acutely toxic compounds to which humans can be exposed. Considerable interest in defining the toxic exposome has been spurred on by the realization that most human injuries, deaths and diseases are directly or indirectly caused by toxic substances found in the air, water, food, home or workplace. The Toxin-Toxin-Target Database (T3DB--www.t3db.ca) is a resource that was specifically designed to capture information about the toxic exposome. Originally released in 2010, the first version of T3DB contained data on nearly 2900 common toxic substances along with detailed information on their chemical properties, descriptions, targets, toxic effects, toxicity thresholds, sequences (for both targets and toxins), mechanisms and references. To more closely align itself with the needs of epidemiologists, toxicologists and exposome scientists, the latest release of T3DB has been substantially upgraded to include many more compounds (>3600), targets (>2000) and gene expression datasets (>15,000 genes). It now includes extensive data on 'normal' toxic compound concentrations in human biofluids as well as detailed chemical taxonomies, informative chemical ontologies and a large number of referential NMR, MS/MS and GC-MS spectra. This manuscript describes the most recent update to the T3DB, which was previously featured in the 2010 NAR Database Issue.

Comparison of hematological alterations and markers of B-cell activation in workers exposed to benzene, formaldehyde and trichloroethylene.

Benzene, formaldehyde (FA) and trichloroethylene (TCE) are ubiquitous chemicals in workplaces and the general environment. Benzene is an established myeloid leukemogen and probable lymphomagen. FA is classified as a myeloid leukemogen but has not been associated with non-Hodgkin lymphoma (NHL), whereas TCE has been associated with NHL but not myeloid leukemia. Epidemiologic associations between FA and myeloid leukemia, and between benzene, TCE and NHL are, however, still debated. Previously, we showed that these chemicals are associated with hematotoxicity in cross-sectional studies of factory workers in China, which included extensive personal monitoring and biological sample collection. Here, we compare and contrast patterns of hematotoxicity, monosomy 7 in myeloid progenitor cells (MPCs), and B-cell activation biomarkers across these studies to further evaluate possible mechanisms of action and consistency of effects with observed hematologic cancer risks. Workers exposed to benzene or FA, but not TCE, showed declines in cell types derived from MPCs, including granulocytes and platelets. Alterations in lymphoid cell types, including B cells and CD4+ T cells, and B-cell activation markers were apparent in workers exposed to benzene or TCE. Given that alterations in myeloid and lymphoid cell types are associated with hematological malignancies, our data provide biologic insight into the epidemiological evidence linking benzene and FA exposure with myeloid leukemia risk, and TCE and benzene exposure with NHL risk.

Adductomics Pipeline for Untargeted Analysis of Modifications to Cys34 of Human Serum Albumin.

An important but understudied class of human exposures is comprised of reactive electrophiles that cannot be measured in vivo because they are short-lived. An avenue for assessing these meaningful exposures focuses on adducts from reactions with nucleophilic loci of blood proteins, particularly Cys34 of human serum albumin, which is the dominant scavenger of reactive electrophiles in serum. We developed an untargeted analytical scheme and bioinformatics pipeline for detecting, quantitating, and annotating Cys34 adducts in tryptic digests of human serum/plasma. The pipeline interrogates tandem mass spectra to find signatures of the Cys34-containing peptide, obtains accurate masses of putative adducts, quantitates adduct levels relative to a "housekeeping peptide", and annotates modifications based on a combination of retention time, accurate mass, elemental composition, and database searches. We used the adductomics pipeline to characterize 43 adduct features in archived plasma from healthy human subjects and found several that were highly associated with smoking status, race, and other covariates. Since smoking is a strong risk factor for cancer and cardiovascular disease, our ability to discover adducts that distinguish smokers from nonsmokers with untargeted adductomics indicates that the pipeline is suitable for use in epidemiologic studies. In fact, adduct features were both positively and negatively associated with smoking, indicating that some adducts arise from reactions between Cys34 and constituents of cigarette smoke (e.g., ethylene oxide and acrylonitrile) while others (Cys34 oxidation products and disulfides) appear to reflect alterations in the serum redox state that resulted in reduced adduct levels in smokers.

Chromosome-wide aneuploidy study of cultured circulating myeloid progenitor cells from workers occupationally exposed to formaldehyde.

Formaldehyde (FA) is an economically important industrial chemical to which millions of people worldwide are exposed environmentally and occupationally. Recently, the International Agency for Cancer Research concluded that there is sufficient evidence that FA causes leukemia, particularly myeloid leukemia. To evaluate the biological plausibility of this association, we employed a chromosome-wide aneuploidy study approach, which allows the evaluation of aneuploidy and structural chromosome aberrations (SCAs) of all 24 chromosomes simultaneously, to analyze cultured myeloid progenitor cells from 29 workers exposed to relatively high levels of FA and 23 unexposed controls. We found statistically significant increases in the frequencies of monosomy, trisomy, tetrasomy and SCAs of multiple chromosomes in exposed workers compared with controls, with particularly notable effects for monosomy 1 [P = 6.02E-06, incidence rate ratio (IRR) = 2.31], monosomy 5 (P = 9.01E-06; IRR = 2.24), monosomy 7 (P = 1.57E-05; IRR = 2.17), trisomy 5 (P = 1.98E-05; IRR = 3.40) and SCAs of chromosome 5 (P = 0.024; IRR = 4.15). The detection of increased levels of monosomy 7 and SCAs of chromosome 5 is particularly relevant as they are frequently observed in acute myeloid leukemia. Our findings provide further evidence that leukemia-related cytogenetic changes can occur in the circulating myeloid progenitor cells of healthy workers exposed to FA, which may be a potential mechanism underlying FA-induced leukemogenesis.

Concentrations of Persistent Organic Pollutants in California Children's Whole Blood and Residential Dust.

We evaluated relationships between persistent organic pollutant (POP) levels in the blood of children with leukemia and POP levels in dust from their household vacuum cleaners. Blood and dust were collected from participants of the California Childhood Leukemia Study at various intervals from 1999 to 2007 and analyzed for two polybrominated diphenyl ethers (PBDEs), two polychlorinated biphenyls (PCBs), and two organochlorine pesticides using gas chromatography-mass spectrometry. Due to small blood sample volumes (100 µL), dichlorodiphenyldichloroethylene (DDE) and BDE-153 were the only analytes with detection frequencies above 70%. For each analyte, depending on its detection frequency, a multivariable linear or logistic regression model was used to evaluate the relationship between POP levels in blood and dust, adjusting for child's age, ethnicity, and breastfeeding duration; mother's country of origin; household annual income; and blood sampling date. In linear regression, concentrations of BDE-153 in blood and dust were positively associated; whereas, DDE concentrations in blood were positively associated with breastfeeding, maternal birth outside the U.S., and Hispanic ethnicity, but not with corresponding dust-DDE concentrations. The probability of PCB-153 detection in a child's blood was marginally associated with dust-PCB-153 concentrations (p = 0.08) in logistic regression and significantly associated with breastfeeding. Our findings suggest that dust ingestion is a source of children's exposure to certain POPs.

Concentrations of persistent organic pollutants in California women's serum and residential dust.

BACKGROUND: Humans are exposed to persistent organic pollutants (POPs) through various routes, including consumption of contaminated food and accidental ingestion of settled dust. OBJECTIVES: We aimed to identify key routes of exposure to organochlorine pesticides, polychlorinated biphenyls (PCBs), and polybrominated diphenyl ethers (PBDEs) in California women of reproductive age. METHODS: Blood was collected from 48 mothers participating in the California Childhood Leukemia Study from 2006 to 2007 and analyzed for POPs using gas chromatography-mass spectrometry. Multivariable linear regression models of natural-log transformed serum concentrations were used to identify determinants of exposure from available questionnaire information on dietary habits, reproductive history, and demographic characteristics, as well as vacuum cleaner dust-POP levels. RESULTS: After adjusting for blood lipid levels, age, body mass index, cumulative lactation, and sampling date, serum concentrations of multiple major PCBs were positively associated with fish consumption, but not dust-PCB levels. After adjusting for blood lipid levels, Hispanic ethnicity, country of origin, and household annual income, serum concentrations of multiple major PBDEs were positively associated with dust-PBDE levels. CONCLUSIONS: Our findings suggest that the relative contribution of specific exposure routes to total POP intake varies by chemical class, with dust being a relatively important source of PBDEs and diet being a relatively important source of PCBs.

Effect of wrist and interphalangeal thumb movement on zone T2 flexor pollicis longus tendon tension in a human cadaver model.

INTRODUCTION: Therapy after flexor pollicis longus (FPL) repair typically mimics finger flexor management, but this ignores anatomic and biomechanical features unique to the FPL. PURPOSE OF THE STUDY: We measured FPL tendon tension in zone T2 to identify biomechanically appropriate exercises for mobilizing the FPL. METHODS: Eight human cadaver hands were studied to identify motions that generated enough force to achieve FPL movement without exceeding hypothetical suture strength. RESULTS: With the carpometacarpal and metacarpophalangeal joints blocked, appropriate forces were produced for both passive interphalangeal (IP) motion with 30° wrist extension and simulated active IP flexion from 0° to 35° with the wrist in the neutral position. DISCUSSION: This work provides a biomechanical basis for safely and effectively mobilizing the zone T2 FPL tendon. CONCLUSION: Our cadaver study suggests that it is safe and effective to perform early passive and active exercise to an isolated IP joint. LEVEL OF EVIDENCE: NA.