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Previous reports have documented an attenuated p53 response to DNA damage in hepatocytes isolated from enzyme-altered foci (EAF). Here, we have studied this p53 response in vivo in rats with EAF. These animals received repeated doses of diethylnitrosamine (DEN) for 6 weeks and a challenging dose 24 h before death. Liver sections were then analysed using an immunohistochemical procedure for p53, or a double-staining procedure for p53 and glutathione-S-transferase pi (GST-P). In control rats or rats with EAF not given the challenging dose of DEN, there was no p53 staining. In control rats, only given the challenging dose of DEN, there was a centrilobular p53 nuclear staining that co-localized with TUNEL staining. In an experiment involving four rats with EAF 389 ± 39 hepatocytes/mm2 of non-EAF tissue stained positively for p53, while the corresponding value for EAF tissue was 27.6 ± 7.5. Thus, p53-positive cells were 14.6-fold more frequent in non-EAF than in EAF tissue. In many EAF no p53-positive cells were seen at all and 83% of the EAF demonstrated <20% of the number of p53-positive cells seen in non-EAF tissue. Very few EAF had as high a proportion of p53-positive cells as did the average non-EAF tissue. EAF >0.06 mm2 had significantly fewer p53-positive cells than smaller EAF. The ratio of p53 expression in non-EAF tissue and larger EAF was 32.6. In a control experiment, four EAF-bearing rats were used as donors to prepare primary cultures of hepatocytes. After 24 h of exposure to DEN, many of the cultured cells became p53-positive. Among GST-P-negative hepatocytes, 12.8% were p53-positive, whereas only 0.25% of the GST-P-positive hepatocytes were p53-positive. Literature data suggest that the altered xenobiotic metabolism in EAF may give rise to a 3-4 fold difference in DNA damage between non-EAF and EAF tissues. It is concluded that GST-P-positive EAF hepatocytes have an attenuated p53 response to DNA damage. This attenuated response may facilitate clonal expansion of EAF under stress induced by DNA-damaging chemicals. [ABSTRACT FROM PUBLISHER]

Presents a letter to the editor about toluene diisocynates.

Abstract Background Many practical tasks in biomedicine require accessing specific types of information in scientific literature; e.g. information about the results or conclusions of the study in question. Several schemes have been developed to characterize such information in scientific journal articles. For example, a simple section-based scheme assigns individual sentences in abstracts under sections such as Objective, Methods, Results and Conclusions. Some schemes of textual information structure have proved useful for biomedical text mining (BIO-TM) tasks (e.g. automatic summarization). However, user-centered evaluation in the context of real-life tasks has been lacking. Methods We take three schemes of different type and granularity - those based on section names, Argumentative Zones (AZ) and Core Scientific Concepts (CoreSC) - and evaluate their usefulness for a real-life task which focuses on biomedical abstracts: Cancer Risk Assessment (CRA). We annotate a corpus of CRA abstracts according to each scheme, develop classifiers for automatic identification of the schemes in abstracts, and evaluate both the manual and automatic classifications directly as well as in the context of CRA. Results Our results show that for each scheme, the majority of categories appear in abstracts, although two of the schemes (AZ and CoreSC) were developed originally for full journal articles. All the schemes can be identified in abstracts relatively reliably using machine learning. Moreover, when cancer risk assessors are presented with scheme annotated abstracts, they find relevant information significantly faster than when presented with unannotated abstracts, even when the annotations are produced using an automatic classifier. Interestingly, in this user-based evaluation the coarse-grained scheme based on section names proved nearly as useful for CRA as the finest-grained CoreSC scheme. Conclusions We have shown that existing schemes aimed at capturing information structure of scientific documents can be applied to biomedical abstracts and can be identified in them automatically with an accuracy which is high enough to benefit a real-life task in biomedicine.

Rehabilitation after an anterior cruciate ligament (ACL) reconstruction requires patience, devotion, and discipline. Rehabilitation should be individualized to each patient's specific need and sport. Return to sport is a continuum throughout the rehabilitation, and patients should not return to performance before passing a battery of muscle function tests and patient-reported outcomes, as well as change of direction-specific tests. Return to full participation should be an agreement between the patient, physical therapist, surgeon, and coach. For minimal risk for second ACL injury, patients should continue with maintenance and prevention training even after returning to sport., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The relationship between hamstring strength and hop performance after anterior cruciate ligament (ACL) reconstruction with hamstring tendon (HT) autografts has not been well elucidated. The aim was to investigate the relationship between eccentric hamstring strength, assessed with the NordBord, and concentric hamstring strength, assessed with the Biodex, with hop performance at 8 and 12 months after ACL reconstruction., Methods: Registry study. Patients ≥ 16 years who had undergone primary ACL reconstruction with HT autograft, followed by muscle strength and hop tests at 8 and 12 months were included. Correlations of the relative hamstring strength (Nm/kg or N/kg) and limb symmetry index (LSI) with hop performance were analyzed. Pearson's correlation coefficient, and coefficient of determination (r 2 ) were used for statistical analysis., Results: A total of 90 patients were included, of which 48 (53%) were women. The mean age at ACL reconstruction was 27.0 ± 8.0 years. Relative hamstring strength had significant positive correlations with hop performance, ranging from r = 0.25-0.66, whereas hamstring strength LSI had significant positive correlations which ranged from r = 0.22-0.37 at 8 and 12 months after ACL reconstruction. At 12 months, the relative hamstring strength in the Biodex explained 32.5-43.6% of the hop performance in vertical hop height, hop for distance relative to height, and the total number of side hops, whereas the relative hamstring strength in the NordBord explained 15.2-23.0% of the hop performance., Conclusion: The relative hamstring strength in the Biodex test explained 32.5-43.6% of the hop performance, whereas the relative hamstring strength in the NordBord explained 15.2-23.0%. Thus, our findings suggest that relative hamstring strength, especially in the hip-flexed position may be a better indicator of hop performance at 8 and 12 months after ACL reconstruction in patients treated with HT autograft., (© 2024. The Author(s).)

Objective: Comparison of knee flexor strength limb symmetry index (LSI) between the NordBord-test and the Biodex-test, and to determine the relationship between knee flexor strength and function in patients 2 and 5 years after anterior cruciate ligament reconstruction (ACL-R) with hamstring tendon (HT) autografts., Design: Observational registry study., Setting: Primary care., Patients: Cross-sectional data from 96 patients (55% women) participating in a rehabilitation-registry after ACL-R with HT autografts., Main Outcome Measures: Comparison of knee flexor strength symmetry between the Biodex-test and the NordBord-test. Secondly, the relationship between knee flexor strength test and perceived knee function, activity level, and hop performance., Results: The NordBord-test demonstrated greater strength deficits compared to the Biodex-test with a mean difference of 12.5% ± 15.1% 95 % CI [8.1; 16.9%] at 2 years, and 11.1% ± 11.9% 95 % CI [7.7; 14.6 %] at 5 years after ACL-R. Relative concentric knee flexor strength (Nm/kg) in the Biodex demonstrated significant weak-to-moderate correlations with activity level and hop performance (r = 0.33-0.67) at 2 and 5 years., Conclusion: The NordBord-test identified deficits in knee flexor strength LSI not seen with the Biodex-test at 2 and 5 years after ACL-R. No significant correlations were found between the persistent knee flexor strength asymmetry and perceived function, activity level or hop performance., Competing Interests: Declaration of Competing interest KS is a board member of Getinge AB. The authors declare that they have no conflict of interest in the content of the present study., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Whether there is a difference in harvesting the semitendinosus tendon alone (S) or in combination with the gracilis tendon (SG) for the recovery of knee flexor strength after anterior cruciate ligament (ACL) reconstruction remains inconclusive. Therefore, this study aimed to assess the recovery of knee flexor strength based on the autograft composition, S or SG autograft at 6, 12, and ≥ 24 months after ACL reconstruction., Methods: A systematic review and meta-analysis was conducted following the PRISMA guidelines. A comprehensive search was performed encompassing the Cochrane Library, Embase, Medline, PEDRo and AMED databases from inception to January 2023. Inclusion criteria were human clinical trials published in English, comprised of randomized controlled trials (RCTs), longitudinal cohort-, cross-sectional and case-control studies that compared knee flexor strength recovery between S and SG autografts in patients undergoing primary ACL reconstruction. Isokinetic peak torques were summarized for angular velocities of 60°/s, 180°/s, and across all angular velocities, assessed at 6, 12, and ≥ 24 months after ACL reconstruction. A random-effects model was used with standardized mean differences and 95% confidence intervals. Risk of bias was assessed with the RoBANS for non-randomized studies and the Cochrane RoB 2 tool for RCTs. Certainty of evidence was appraised using the GRADE working group methodology., Results: Among the 1,227 patients from the 15 included studies, 604 patients received treatment with S autograft (49%), and 623 received SG autograft (51%). Patients treated with S autograft displayed lesser strength deficits at 6 months across all angular velocities d = -0.25, (95% CI -0.40; -0.10, p = 0.001). Beyond 6 months after ACL reconstruction, no significant difference was observed between autograft compositions., Conclusion: The harvest of S autograft for ACL reconstruction yields superior knee flexor strength recovery compared to SG autograft 6 months after ACL reconstruction, irrespective of angular velocity at isokinetic testing. However, the clinical significance of the observed difference in knee flexor strength between autograft compositions at 6 months is questionable, given the very low certainty of evidence and small effect size. There was no significant difference in knee flexor strength recovery between autograft compositions beyond 6 months after ACL reconstruction., Trial Registration: CRD42022286773., (© 2024. The Author(s).)

Background: The stress on the anterior cruciate ligament (ACL) induced by the quadriceps can be attenuated by activation of the hamstrings by exerting an opposing torque to the anterior translation of tibia. Consequently, considering the ratio between strength of the hamstrings-to-quadriceps (HQ-ratio) may be of value to reduce the odds of second ACL injuries. The objective was therefore to evaluate (1) the association between HQ-ratio and the occurrence of a second ACL injury in patients after ACL-reconstruction within 2 years of return to preinjury sport level and (2) to compare the HQ-ratio between males and females after ACL reconstruction., Methods: Patients who had undergone primary ACL reconstruction and participated in knee-strenuous activity preinjury were included. Demographics, the occurrence of a second ACL injury, and muscle strength test results before returning to preinjury sport level were extracted from a rehabilitation registry. The endpoint was set at a second ACL injury or 2 years after return to preinjury sport level. A multivariable logistic regression was used to analyze the association between the HQ-ratio and a second ACL injury., Results: A total of 574 patients (50.0% female) with a mean age of 24.0 ± 9.4 years at primary ACL reconstruction were included. In the univariable logistic regression analysis, the odds of sustaining a second ACL injury decreased by 3% for every 1% increase in the HQ-ratio (OR 0.97 [95% CI 0.95-1.00], p = 0.025). After adjusting for the time from reconstruction to return to preinjury sport level, sex, preinjury sport level, graft choice, age, and body mass index, the results were no longer significant (OR 0.98 [95% CI 0.95-1.01], p = 0.16). Females had a higher HQ-ratio compared with males for both the ACL-reconstructed and uninjured side (3.7% [95% CI 5.7; 1.8%], p = 0.0002 and 3.3% [95% CI 4.6; 2.1], p < 0.001, respectively)., Conclusion: The HQ-ratio did not significantly affect the odds for sustaining a second ACL injury upon return to preinjury sports level after primary ACL reconstruction. Females had a significant higher HQ-ratio than males for both the ACL reconstructed and uninjured side., (© 2024. The Author(s).)

Background: The Otsu method and the Chan-Vese model are two methods proven to perform well in determining volumes of different organs and specific tissue fractions. This study aimed to compare the performance of the two methods regarding segmentation of active thyroid gland volumes, reflecting different clinical settings by varying the parameters: gland size, gland activity concentration, background activity concentration and gland activity concentration heterogeneity., Methods: A computed tomography was performed on three playdough thyroid phantoms with volumes 20, 35 and 50 ml. The image data were separated into playdough and water based on Hounsfield values. Sixty single photon emission computed tomography (SPECT) projections were simulated by Monte Carlo method with isotope Technetium-99 m ([Formula: see text]Tc). Linear combinations of SPECT images were made, generating 12 different combinations of volume and background: each with both homogeneous thyroid activity concentration and three hotspots of different relative activity concentrations (48 SPECT images in total). The relative background levels chosen were 5 %, 10 %, 15 % and 20 % of the phantom activity concentration and the hotspot activities were 100 % (homogeneous case) 150 %, 200 % and 250 %. Poisson noise, (coefficient of variation of 0.8 at a 20 % background level, scattering excluded), was added before reconstruction was done with the Monte Carlo-based SPECT reconstruction algorithm Sahlgrenska Academy reconstruction code (SARec). Two different segmentation algorithms were applied: Otsu's threshold selection method and an adaptation of the Chan-Vese model for active contours without edges; the results were evaluated concerning relative volume, mean absolute error and standard deviation per thyroid volume, as well as dice similarity coefficient., Results: Both methods segment the images well and deviate similarly from the true volumes. They seem to slightly overestimate small volumes and underestimate large ones. Different background levels affect the two methods similarly as well. However, the Chan-Vese model deviates less and paired t-testing showed significant difference between distributions of dice similarity coefficients (p-value [Formula: see text])., Conclusions: The investigations indicate that the Chan-Vese model performs better and is slightly more robust, while being more challenging to implement and use clinically. There is a trade-off between performance and user-friendliness., (© 2024. The Author(s).)

This article addresses issues of importance for occupational exposure limits (OELs) and chemical carcinogens with a focus on non-threshold carcinogens. It comprises scientific as well as regulatory issues. It is an overview, not a comprehensive review. A central topic is mechanistic research and insights, and its implications for cancer risk assessment. Alongside scientific advancements, the approaches of hazard identification and qualitative and quantitative risk assessment have developed over the years. The key steps in a quantitative risk assessment are outlined, with special attention given to the dose-response assessment and the derivation of an OEL using risk calculations or default assessment factors. The work procedures of several bodies performing cancer hazard identifications and quantitative risk assessments, as well as regulatory procedures to derive OELs for non-threshold carcinogens, are presented. Non-threshold carcinogens for which the European Union (EU) introduced binding OELs in 2017-2019 serve as illustrations together with some currently used strategies in the EU and elsewhere. Available knowledge supports the derivation of health-based OELs (Hb-OELs) for non-threshold carcinogens, and the use of a risk-based approach with low-dose linear extrapolation (linear non-threshold, LNT) as the default for non-threshold carcinogens. However, there is a need to develop methods that allow recent years' advances in cancer research to be used for improving risk estimates. It is recommended that defined risk levels (terminology and numerical values) are harmonised, and that both collective and individual risks are considered and clearly communicated. Socioeconomic aspects should be dealt with transparently and separated from the scientific health risk assessment.

Background: Treatment volume can impact outcomes after surgical procedures of the knee between surgeons with high- and low-patient-volumes. However, the difference between physical therapeutic clinics with high- and low-volumes has not been widely researched. This registry study aims to investigate how patient volume affects knee function outcomes after anterior cruciate ligament (ACL) reconstruction at physical therapy (PT) clinics in terms of odds for a second ACL injury, return to pre-injury level of activity, perceived knee function, and recovery of strength and hop performance., Method: Data were extracted from the Project ACL, a local rehabilitation registry. High- and low-volume clinics were defined based on the number of patients who attended different clinics. High-volume clinics were defined as those with > 100 patient registrations in Project ACL during the study period while low-volume clinics were those with ≤ 100 patient registrations. High- and low-volume clinics were compared, based on muscle function and patient-reported outcomes across 4 follow-ups, 2-, 4-, 8-, and 12 months, during the first year after ACL reconstruction, and odds of second ACL injury up to 2 years after ACL reconstruction., Result: Of the 115 rehabilitation clinics included, 111 were classified as low-volume clinics and included 733 patients, and 4 as high-volume clinics which included 1221 patients. There were 31 (1.6%) second ACL injuries to the ipsilateral or contralateral side within the first 12 months and 68 (4.0%) within 2 years. No difference in the incidence of a second ACL injury, within 12 months follow-up odds ratio (OR) 0.95 [95% CI 0.46-1.97] or within 2 years follow-up OR 1.13 [95% CI 0.68-1.88], was found between high- and low-volume clinics. There were early (2 months) and non-clinically relevant differences in patient-reported outcomes (PROs) and physical activity levels early after ACL reconstruction in favor of high-volume clinics. One year after ACL reconstruction, no differences were observed between high- and low-volume clinics in terms of PROs, muscle function, and return to pre-injury level of activity., Conclusion: No clinically relevant difference in the incidence of secondary ACL injuries in patients who underwent rehabilitation after ACL reconstruction at high- or low-volume physical therapist clinics was found. In addition, no clinically relevant differences in outcomes were found during the first year in terms of patient-reported outcomes, recovery of muscle function, or return to pre-injury level of activity., (© 2023. The Author(s).)

Background: Generalised joint hypermobility (GJH) has been associated with an increased risk of suffering an anterior cruciate ligament (ACL) injury. Patients with GJH exhibit lower muscle strength and poorer scores for patient-reported outcomes after ACL reconstruction, compared with patients without GJH. The aim of this study was to examine differences in the percentages of patients who return to sport (RTS) or pre-injury level of activity (RTP), muscle function and patient-reported outcomes at the time of RTS or RTP, as well as the time of RTS or RTP in patients with GJH compared with patients without GJH in the first two years after ACL reconstruction., Methods: This prospective study used data from an ACL- and rehabilitation-specific register located in Gothenburg, Sweden. Patients aged between 16 and 50, who had a primary ACL injury treated with reconstruction, were included. Data up to two years after ACL reconstruction were used and consisted of achieving RTS and RTP, results from isokinetic muscle function tests for knee extension and flexion and patient-reported outcomes (Knee Self-Efficacy Scale, Knee injury and Osteoarthritis Outcome Score and ACL-Return to Sport after Injury scale) at the time of RTS, as well as the time of RTP. A Beighton Score of ≥ 5/9 was used to define GJH. A Tegner Activity Scale of ≥ 6 was used to define RTS, while a Tegner equal to or above pre-injury level was used to define RTP., Results: A total of 1,198 patients (54.7% women) with a mean age of 28.5 ± 8.6 years were included. A smaller proportion of patients with GJH achieved RTS compared with patients without GJH (49.2% vs. 57.3%, Odds ratio: 0.720, p = 0.041). Furthermore, patients with GJH were marginally less symmetrical on the knee extension strength test, expressed as a Limb Symmetry Index, at the time of RTP compared with patients without GJH (87.3 ± 13.5 vs. 91.7 ± 14.3, Cohen's d = 0.142, p = 0.022). No further differences were found between groups regarding any muscle function tests or patient-reported outcomes., Conclusion: A smaller proportion of patients with GJH achieved RTS compared with patients without GJH. Patients with GJH displayed less symmetrical knee extension strength at the time of RTP compared with patients without GJH., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Patients report psychological barriers as important when returning to sport, however, psychological outcome measures are seldom included in return to sport (RTS) assessment. There is a need for clinical trials to integrate psychological patient-reported outcomes (PROs) in return to sport batteries assessing patients treated with ACL reconstruction., Objective: The aim of this study was to determine the association between passing clinical tests of muscle function and psychological PROs and sustaining a second ACL injury in patients who RTS after primary ACL reconstruction., Design: Retrospective Cohort study., Methods: Patients' sex, age, height and weight, and the results of strength and hop tests, as well as answers to PRO's (including Tegner activity scale, the ACL Return to Sport after Injury scale (ACL-RSI) as well as the Quality of Life (QoL) subscale of the Knee injury and Osteoarthritis Outcome Score [KOOS]), were extracted from a rehabilitation-specific registry. Four different test batteries comprising muscle function tests and PROs were created to assess whether patients were ready to RTS. Passing each of the test batteries (yes/no) was used as an independent variable. A multivariable Cox proportional hazard model analysis was performed, with sustaining a second ACL injury (either ipsi- or contralateral; yes/no) within two years of RTS as the dependent variable., Results: A total of 419 patients (male, n=214; 51%) were included, of which 51 (12.2%) suffered a second ACL injury within the first two years after RTS. There were no differences in passing rates in the different RTS test batteries comprising muscle function tests and PROs for patients who suffered a second ACL injury compared to patients who did not., Conclusion: No association between passing the RTS clinical tests batteries comprising muscle function and psychological PROs used, and the risk of a second ACL injury could be found., Level of Evidence: 3©The Author(s)., Competing Interests: Author KS reports he is a Member of the Board of Directors of Getinge AB (publ).

Background: Anterior cruciate ligament (ACL) injuries are common sports-related injuries with a high risk of reinjury after return to sport (RTS). Rehabilitation aims to regain symmetrical knee strength and function to minimize the risk of a second ACL injury after RTS., Purpose: To determine the effect of absolute quadriceps and hamstring strength, normalized by body weight, on the risk of a second ACL injury during the first 2 years after RTS in patients who have undergone ACL reconstruction (ACLR)., Study Design: Cohort study; Level of evidence, 3., Methods: Data from patients after index ACLR at the time of RTS were extracted from a rehabilitation registry-Project ACL. Patients who had performed isokinetic tests for quadriceps and hamstring strength and hop tests before RTS were included. The endpoint was a second ACL injury or a follow-up of 2 years after RTS after ACLR., Results: A total of 835 patients (46% women), with a mean age of 23.9 ± 7.7 years, were included. During the study period, 69 (8.3%) second ACL injuries (ipsilateral and contralateral) occurred. Greater relative quadriceps strength in the injured leg increased the risk of a second ACL injury (relative risk [RR], 1.69 [95% CI, 1.05-2.74]; P = .032). In patients who had recovered symmetrical quadriceps strength (limb symmetry index ≥90%), there was no effect of quadriceps strength on the risk of second ACL injury (RR, 1.33 [95% CI, 0.69-2.56]; P = .39). Quadriceps strength on the healthy side or hamstring strength, regardless of side, had no effect on the risk of a second ACL injury., Conclusion: Greater relative quadriceps strength in the injured leg at the time of RTS after ACLR was associated with an increased risk of a second ACL injury. There was no effect of relative quadriceps strength on the risk of a second ACL injury in patients who had recovered symmetrical quadriceps strength., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: R.S. received salary support from the Local Research and Development Council of Gothenburg and Södra Bohuslän. K.S. is a board member of Getinge AB. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto., (© The Author(s) 2023.)

Background: There is a need for better understanding of how knee flexor strength influence patient-reported outcomes (PROs) after anterior cruciate ligament (ACL) reconstruction. Our aim was to investigate the relationship between the eccentric NordBord test and the seated concentric Biodex test with PROs, during the first year of rehabilitation after ACL reconstruction with hamstring tendon (HT) autograft., Methods: Patients with an index ACL reconstruction with an HT autograft participating in a rehabilitation registry were screened for inclusion. Outcomes of interest were the correlation between absolute (N/kg or Nm/kg) and relative (limb symmetry index) knee flexor strength measured in the NordBord and Biodex with the results of PROs. The significance level was set at p < 0.05 and Pearson's correlation coefficient was used., Results: 137 patients were included (47% women) with a mean age of 24.8 ± 8.4 years. There were non-significant and weak correlations between relative strength for all PROs. Significant and weak correlations between absolute strength in the Biodex with the Knee Self-Efficacy Scale 18 (K-SES 18 ) present at 4 and 8 months, and for the ACL-Return to Sport after Injury scale (ACL-RSI) at 12 months was observed, accounting for 8.4-15.7% of the variance. Significant and weak correlations between absolute strength in the Nordbord with the Knee injury and Osteoarthritis Outcome Scale subscale Sports and Recreation at 4 months, the K-SES 18 present and the ACL-RSI at 8 months were observed, accounting for 9.4-14.4% of the variance., Conclusion: Absolute knee flexor strength relative to bodyweight for both the Biodex and NordBord test appeared to have a stronger relationship with perceived knee function than relative knee flexor strength, although the observed correlations were weak., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Crystalline silica particles (CSi) are an established human carcinogen, but it is not clear how these particles cause necessary mutations. A well-established scenario includes inflammation caused by retained particles in the bronchioles, activated macrophages, and reactive oxygen species (ROS) that cause DNA damage. In previous studies, we showed that CSi in contact with the plasma membrane of human bronchial epithelium induced double strand breaks within minutes. A signaling pathway implicating the ATX-LPA axis, Rac1, NLRP3, and mitochondrial depolarization upstream of DSB formation was delineated. In this paper, we provide in vitro and in vivo evidence that this signaling pathway triggers endonuclease G (EndoG) translocation from the mitochondria to the nucleus. The DNA damage is documented as γH2AX and p53BP1 nuclear foci, strand breaks in the Comet assay, and as micronuclei. In addition, the DNA damage is induced by low doses of CSi that do not induce apoptosis. By inhibiting the ATX-LPA axis or by EndoG knockdown, we prevent EndoG translocation and DSB formation. Our data indicate that CSi in low doses induces DSBs by sub-apoptotic activation of EndoG, adding CSi to a list of carcinogens that may induce mutations via sub-apoptotic and "minority MOMP" effects. This is the first report linking the ATX-LPA axis to this type of carcinogenic effect.

Background: Psychological patient-reported outcomes (PROs) are recommended for use in test batteries to aid in decision-making, regarding whether patients are well prepared to return to sports (RTS) after anterior cruciate ligament (ACL) reconstruction. However, the values that should be regarded as "pass" or "fail" are still unclear., Purpose: This study aimed to identify cut-off values for three commonly used psychological PROs that could differentiate patients who suffer a second ACL injury from patients who do not within two years of RTS in patients after ACL reconstruction with respect to recovery of symmetrical quadriceps strength., Study Design: Diagnostic/prognostic study., Methods: Demographic data, isokinetic strength test data for quadriceps, as well as results for the ACL-Return to Sport after Injury scale (ACL-RSI), Knee Injury and Osteoarthritis Outcome Score (KOOS) Quality of Life, and Function in Sport and Recreation sub-scales, and the 18-item version of the Knee Self-Efficacy Scale (K-SES 18 ) were extracted from a registry. Receiver operating characteristic (ROC) curves were calculated for each PRO. Accuracy of the cut-offs was presented with two summary measures for the ROC: the area under the curve (AUC) and Youden index., Results: In total, 641 (355 men, 61%) patients (24.8 [SD 7.6] year old at ACL reconstruction) were included. The cut-off values were not able to differentiate patients who suffered a second ACL injury up to 24 months after RTS and ACL reconstruction from patients who did not. Additionally, achieving symmetrical quadriceps strength did not improve the cut-off psychometric properties., Conclusion: Since cut-off values could not differentiate between patients who suffered a second ACL injury and those who did not, clinicians should not rely only on cut-off values or a single PRO of those analyzed in this study when making decisions on which patients are at risk of experiencing a second ACL injury when returning to sports after ACL reconstruction., Level of Evidence: Level 3., Competing Interests: Authors declare no conflict of interest.

Objective: To investigate the recovery of knee flexor muscle strength evaluated with a Nordic hamstring eccentric test (NordBord) compared with an isokinetic concentric test (Biodex) during the first year after anterior cruciate ligament (ACL) reconstruction using a hamstring tendon autograft., Design: Prospective observational registry study; level of evidence, 3., Setting: Primary care., Participants: Cross-sectional data of 127 patients (45% women, mean age 24.9 ± 8.1 years) were extracted from a rehabilitation outcome registry at 10 weeks and 4, 8 and 12 months after ACL reconstruction with hamstring tendon autograft., Main Outcome Measures: All patients performed a concentric Biodex test, and an eccentric NordBord test on the same occasion or within seven days of the concentric test. The primary outcome was the limb symmetry index between the respective tests., Results: A greater knee flexor symmetry deficit was observed with the eccentric test compared with the concentric test at all follow-ups with clinically relevant differences at 4 (11.8% ± 12.7% [CI 7.8-15.8%]) and 8 months (13.4 ± 11.9 [CI 9.7-17.2%]., Conclusion: The eccentric NordBord test was able to identify clinically relevant deficits in knee flexor strength symmetry that were not identified by gold standard isokinetic concentric testing during the first year among patients treated with an ACL reconstruction using a hamstring tendon autograft., Competing Interests: Declaration of competing interest None., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Sensitization to a contact allergen brings with it a lifelong risk to develop allergic contact dermatitis. Inflammation is an important part of the skin sensitizing mechanism, and understanding how different haptens stimulate the immune system, as well as the role played by different cell types present in skin, may be helpful for developing optimized in vitro models for risk assessment of new chemicals or mixtures. The aim of this study was to compare the cytokine profile following exposure of cells representing keratinocytes (HaCaT), monocytes (THP-1) and a co-culture of these cells to three clinically important skin sensitizers: cobalt (II) chloride (CoCl 2 ), methylisothiazolinone (MI) and p-phenylenediamine (PPD). Secretion of ten pro-inflammatory cytokines was measured using multiplexing. The results showed that the cytokine response differed substantially between the three cell assays. CoCl 2 caused an increase of IL-8 in HaCaT cells, while the induction of also IL-13 and IL-1β was observed in THP-1 cells and co-cultures. MI induced six cytokines in HaCaT cells but only IL-1β in the THP-1 cells and four cytokines in the co-culture. Interestingly, the IL-1β response was massive in the co-culture. PPD caused release of IL-1β in all three models as well as IL-8 in the co-culture. Control experiments with two non-sensitizers and irritants (lactic acid and sodium dodecyl sulfate) showed no effect on IL-8 or IL-1β in the co-culture. Taken together, results from this exploratory analysis show unique cytokine profiles dependent on the type of hapten and cell model. Importantly, all three haptens triggered secretion of IL-1β and IL-8 in a co-culture of HaCaT cells and THP-1 cells, representing the most robust test system.

Background: Cancer risk assessment of complex exposures, such as exposure to mixtures of polycyclic aromatic hydrocarbons (PAHs), is challenging due to the diverse biological activities of these compounds. With the help of text mining (TM), we have developed TM tools-the latest iteration of the Cancer Risk Assessment using Biomedical literature tool (CRAB3) and a Cancer Hallmarks Analytics Tool (CHAT)-that could be useful for automatic literature analyses in cancer risk assessment and research. Although CRAB3 analyses are based on carcinogenic modes of action (MOAs) and cover almost all the key characteristics of carcinogens, CHAT evaluates literature according to the hallmarks of cancer referring to the alterations in cellular behavior that characterize the cancer cell., Objectives: The objective was to evaluate the usefulness of these tools to support cancer risk assessment by performing a case study of 22 European Union and U.S. Environmental Protection Agency priority PAHs and diesel exhaust and a case study of PAH interactions with silica., Methods: We analyzed PubMed literature, comprising 57,498 references concerning priority PAHs and complex PAH mixtures, using CRAB3 and CHAT., Results: CRAB3 analyses correctly identified similarities and differences in genotoxic and nongenotoxic MOAs of the 22 priority PAHs and grouped them according to their known carcinogenic potential. CHAT had the same capacity and complemented the CRAB output when comparing, for example, benzo[ a ]pyrene and dibenzo[ a,l ]pyrene. Both CRAB3 and CHAT analyses highlighted potentially interacting mechanisms within and across complex PAH mixtures and mechanisms of possible importance for interactions with silica., Conclusion: These data suggest that our TM approach can be useful in the hazard identification of PAHs and mixtures including PAHs. The tools can assist in grouping chemicals and identifying similarities and differences in carcinogenic MOAs and their interactions. https://doi.org/10.1289/EHP6702.

Autotaxin (ATX) and its product lysophosphatidic acid (LPA) have been implicated in lung fibrosis and cancer. We have studied their roles in DNA damage induced by carcinogenic crystalline silica particles (CSi). In an earlier study on bronchial epithelia, we concluded that ATX, via paracrine signaling, amplifies DNA damage. This effect was seen at 6-16 h. A succeeding study showed that CSi induced NLRP3 phosphorylation, mitochondrial depolarization, double strand breaks (DSBs), and NHEJ repair enzymes within minutes. In the current study we hypothesized a role for the ATX-LPA axis also in this rapid DNA damage. Using 16HBE human bronchial epithelial cells, we show ATX secretion at 3 min, and that ATX inhibitors (HA130 and PF8380) prevented both CSi-induced mitochondrial depolarization and DNA damage (detected by γH2AX and Comet assay analysis). Experiments with added LPA gave similar rapid effects as CSi. Furthermore, Rac1 was activated at 3 min, and a Rac1 inhibitor (NSC23766) prevented mitochondrial depolarization and genotoxicity. In mice the bronchial epithelia exhibited histological signs of ATX activation and signs of DSBs (53BP1 positive nuclei) minutes after a single inhalation of CSi. Our data indicate that CSi rapidly activate the ATX-LPA axis and within minutes this leads to DNA damage in bronchial epithelial cells. Thus, ATX mediates very rapid DNA damaging effects of inhaled particles., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Respirable crystalline silica causes lung carcinomas and many thousand future cancer cases are expected in e.g. Europe. Critical questions are how silica causes genotoxicity in the respiratory epithelium and if new cases can be avoided by lowered permissible exposure levels. In this study we investigate early DNA damaging effects of low doses of silica particles in respiratory epithelial cells in vitro and in vivo in an effort to understand low-dose carcinogenic effects of silica particles., Results: We find DNA damage accumulation already after 5-10 min exposure to low doses (5 μg/cm 2 ) of silica particles (Min-U-Sil 5) in vitro. DNA damage was documented as increased levels of γH2AX, pCHK2, by Comet assay, AIM2 induction, and by increased DNA repair (non-homologous end joining) signaling. The DNA damage response (DDR) was not related to increased ROS levels, but to a NLRP3-dependent mitochondrial depolarization. Particles in contact with the plasma membrane elicited a Ser198 phosphorylation of NLRP3, co-localization of NLRP3 to mitochondria and depolarization. FCCP, a mitochondrial uncoupler, as well as overexpressed NLRP3 mimicked the silica-induced depolarization and the DNA damage response. A single inhalation of 25 μg silica particles gave a similar rapid DDR in mouse lung. Biomarkers (CC10 and GPRC5A) indicated an involvement of respiratory epithelial cells., Conclusions: Our findings demonstrate a novel mode of action (MOA) for silica-induced DNA damage and mutagenic double strand breaks in airway epithelial cells. This MOA seems independent of particle uptake and of an involvement of macrophages. Our study might help defining models for estimating exposure levels without DNA damaging effects.

Akt kinase regulates several cellular processes, among them growth, proliferation and survival, and has been correlated to neoplastic disease. We report here crosstalk between several Akt regulatory phosphatases that controls the level of the activated form (phosphorylated) of Akt and affects tumor cell aggressiveness. In prostate cancer cell lines, we observed that transient transfection of PTEN decreased the endogenous level of PHLPPs and in contrast, the transient transfection of PHLPPs decreased the endogenous level of PTEN. Furthermore, silencing of PTEN by siRNA resulted in increased PHLPP levels. This phenomenon was not seen in non-transformed cells or in prostate stem cells. This crosstalk promoted cancer cell invasion and was controlled by epigenetically regulated processes where activation of miRs (miR-190 and miR214), the polycomb group of proteins and DNA methylation were involved. The purinergic P2X4 receptor, which has been shown to have a role in wound healing, was identified to be the mediator of this crosstalk. We also studied prostate stem cells and found this crosstalk in the TGFβ1-activated epithelial-mesenchymal transition (EMT). The crosstalk seemed to be a natural part of EMT. In summary, we identify a crosstalk between Akt phosphatases which is not present in non-transformed prostate cells but occurs in cancer cells and stem cells transformed by TGFβ-1. This crosstalk is important for cellular invasion., Background: Phosphatases regulate the Akt oncogene., Results: Crosstalk between Akt phosphatases in prostate cancer cells and in TGF-β1 activated stem cells but not in non-transformed cells., Conclusion: This back-up mechanism facilitates invasive migration of prostate stem and cancer cells., Significance: Characterization of Akt regulation may lead to a better understanding of tumor development and to novel strategies for treatment., Competing Interests: Declaration of Competing Interest The authors declare that there is no conflict of interest related to this work., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Motivation: The overwhelming size and rapid growth of the biomedical literature make it impossible for scientists to read all studies related to their work, potentially leading to missed connections and wasted time and resources. Literature-based discovery (LBD) aims to alleviate these issues by identifying implicit links between disjoint parts of the literature. While LBD has been studied in depth since its introduction three decades ago, there has been limited work making use of recent advances in biomedical text processing methods in LBD., Results: We present LION LBD, a literature-based discovery system that enables researchers to navigate published information and supports hypothesis generation and testing. The system is built with a particular focus on the molecular biology of cancer using state-of-the-art machine learning and natural language processing methods, including named entity recognition and grounding to domain ontologies covering a wide range of entity types and a novel approach to detecting references to the hallmarks of cancer in text. LION LBD implements a broad selection of co-occurrence based metrics for analyzing the strength of entity associations, and its design allows real-time search to discover indirect associations between entities in a database of tens of millions of publications while preserving the ability of users to explore each mention in its original context in the literature. Evaluations of the system demonstrate its ability to identify undiscovered links and rank relevant concepts highly among potential connections., Availability and Implementation: The LION LBD system is available via a web-based user interface and a programmable API, and all components of the system are made available under open licenses from the project home page http://lbd.lionproject.net., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2018. Published by Oxford University Press.)

Toluene diisocyanate (TDI) is a reactive chemical used in manufacturing plastics. TDI exposure adversely affects workers' health, causing occupational asthma, but individuals differ in susceptibility. We recently suggested a role for signalling mediated by the enzyme autotaxin (ATX) and its product, lysophosphatidic acid (LPA), in TDI toxicity. Here we genotyped 118 TDI-exposed workers for six single-nucleotide polymorphisms (SNPs) in genes encoding proteins implicated in ATX-LPA signalling: purinergic receptor P2X7 (P2RX7), CC motif chemokine ligand 2 (CCL2), interleukin 1β (IL1B), and caveolin 1 (CAV1). Two P2RX7 SNPs (rs208294 and rs2230911) significantly modified the associations between a biomarker of TDI exposure (urinary 2,4-toluene diamine) and plasma LPA; two IL1B SNPs (rs16944 and rs1143634) did not. CAV1 rs3807989 modified the associations, but the effect was not statistically significant (p = 0.05-0.09). In vitro, TDI-exposed bronchial epithelial cells (16HBE14o-) rapidly released ATX and IL-1β. P2X7 inhibitors attenuated both responses, but confocal microscopy showed non-overlapping localizations of ATX and IL-1β, and down-regulation of CAV1 inhibited the ATX response but not the IL-1β response. This study indicates that P2X7 is pivotal for TDI-induced ATX-LPA signalling, which was modified by genetic variation in P2RX7. Furthermore, our data suggest that the TDI-induced ATX and IL-1β responses occur independently., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: Radioembolization is an alternative palliative treatment for hepatocellular carcinoma. Here, we examine the uptake differences between tumor tissue phenotypes and present a cross-section of the absorbed dose throughout a liver tissue specimen., Methods and Materials: A patient with hepatocellular carcinoma was treated with 90 Y radioembolization followed by liver tissue resection. Gamma camera images and autoradiographs were collected and biopsy tissue samples were analyzed using a gamma well counter and light microscopy., Results: An analysis of 25 punched biopsy tissue samples identified 4 tissue regions: Normal tissue, viable tumor tissue with and without infarcted areas, and tumor areas with postnecrotic scar tissue. Autoradiography and biopsy tissue sample measurements showed large dose differences between viable and postnecrotic tumor tissue (159 Gy vs 23 Gy)., Conclusions: Radioembolization of 90 yttrium with resin microspheres produces heterogeneous-absorbed dose distributions in the treatment of unifocal hepatic malignancies that could not be accurately determined with current gamma camera imaging techniques.

Motivation: To understand the molecular mechanisms involved in cancer development, significant efforts are being invested in cancer research. This has resulted in millions of scientific articles. An efficient and thorough review of the existing literature is crucially important to drive new research. This time-demanding task can be supported by emerging computational approaches based on text mining which offer a great opportunity to organize and retrieve the desired information efficiently from sizable databases. One way to organize existing knowledge on cancer is to utilize the widely accepted framework of the Hallmarks of Cancer. These hallmarks refer to the alterations in cell behaviour that characterize the cancer cell., Results: We created an extensive Hallmarks of Cancer taxonomy and developed automatic text mining methodology and a tool (CHAT) capable of retrieving and organizing millions of cancer-related references from PubMed into the taxonomy. The efficiency and accuracy of the tool was evaluated intrinsically as well as extrinsically by case studies. The correlations identified by the tool show that it offers a great potential to organize and correctly classify cancer-related literature. Furthermore, the tool can be useful, for example, in identifying hallmarks associated with extrinsic factors, biomarkers and therapeutics targets., Availability and Implementation: CHAT can be accessed at: http://chat.lionproject.net. The corpus of hallmark-annotated PubMed abstracts and the software are available at: http://chat.lionproject.net/about., Contact: simon.baker@cl.cam.ac.uk., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author 2017. Published by Oxford University Press.)

Silica exposure is a common risk factor for lung cancer. It has been claimed that key elements in cancer development are activation of inflammatory cells that indirectly induce DNA damage and proliferative stimuli in respiratory epithelial cells. We studied DNA damage induced by silica particles in respiratory epithelial cells and focused the role of the signaling enzyme autotaxin (ATX). A549 and 16 bronchial epithelial cells (16HBE) lung epithelial cells were exposed to silica particles. Reactive oxygen species (ROS), NOD-like receptor family pyrin domain containing-3 (NLRP3) inflammasome activation, ATX, ataxia telangiectasia mutated (ATM), and DNA damage (γH2AX, pCHK1, pCHK2, comet assay) were end points. Low doses of silica induced NLRP3 activation, DNA damage accumulation, and ATM phosphorylation. A novel finding was that ATM induced ATX generation and secretion. Not only silica but also rotenone, camptothecin and H2O2 activated ATX via ATM, suggesting that ATX is part of a generalized ATM response to double-strand breaks (DSBs). Surprisingly, ATX inhibition mitigated DNA damage accumulation at later time points (6-16 h), and ATX transfection caused NLRP3 activation and DNA damage. Furthermore, the product of ATX enzymatic activity, lysophosphatidic acid, recapitulated the effects of ATX transfection. These data indicate an ATM-ATX-dependent loop that propagates inflammation and DSB accumulation, making low doses of silica effective inducers of DSBs in epithelial cells. We conclude that an ATM-ATX axis interconnects DSBs with silica-induced inflammation and propagates these effects in epithelial cells. Further studies of this adverse outcome pathway may give an accurate assessment of the lowest doses of silica that causes cancer., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Hepatocellular carcinoma (HCC) is rated as the fifth most common malignancy and third in cancer-related deaths worldwide. Statins, HMG-CoA reductase inhibitors, are potent cholesterol-lowering drugs, and recent epidemiologic evidence suggests that statins prevent aggressive HCC development. Previous experiments revealed that statins downregulate phosphorylated Akt (pAkt). Here, it is demonstrated that atorvastatin decreases nuclear pAkt levels in pancreatic and lung cancer cell lines within minutes, and this rapid effect is mediated by the purinergic P2X receptors. Akt is upregulated by hepatitis viruses and has oncogenic activity in HCC; therefore, we tested the possibility that the P2X-Akt pathway is important for the anticipated anticancer effects of statins in hepatocytes. Atorvastatin decreased hepatitis B virus X protein- and insulin-induced pAkt and pGsk3β (Ser9) levels. Furthermore, Akt-induced lipogenesis was counteracted by atorvastatin, and these statin-induced effects were dependent on P2X receptors. Statin also decreased proliferation and invasiveness of hepatocytes. These data provide mechanistic evidence for a P2X receptor-dependent signaling pathway by which statins decrease pAkt, its downstream phosphorylation target pGsk3β, and lipogenesis in hepatocytes. Implications: The Akt pathway is deregulated and may act as a driver in HCC development; the P2X-Akt signaling pathway may have a role in anticancer effects of statins. Mol Cancer Res; 15(6); 714-22. ©2017 AACR ., (©2017 American Association for Cancer Research.)