Precarious employment in young adulthood and later alcohol-related morbidity: a register-based cohort study.

OBJECTIVES: The prevalence of precarious employment is increasing, particularly among young adults where less is known about the long-term health consequences. The present study aims to test if being precariously employed in young adulthood is associated with an increased risk of alcohol-related morbidity later in life. METHODS: A register-based cohort study was conducted in Sweden. The Swedish Work, Illness, and Labor-market Participation (SWIP) cohort was used to identify individuals who were aged 27 years between 2000 and 2003 (n=339 403). Information on labour market position (precarious employment, long-term unemployment, substandard employment and standard employment relations) was collected for young people 3 years after graduation from school using nationwide registers. Details about alcohol-related morbidity during a 28-year follow-up period were collected from the National Hospital Discharge Register. Data on sex, age, country of birth, education and previous poor health were also obtained from the registers. RESULTS: Young adults in precarious employment had an increased risk of alcohol-related morbidity compared with individuals of the same age in standard employment (HR 1.43, 95% CI 1.32 to 1.55), after adjusting for several important covariates. A stronger association was found among young men who were precariously employed compared with young women. CONCLUSION: This nationwide register-based study conducted in Sweden with a long-term follow-up suggests that being precariously employed in young adulthood is associated with an increased risk of alcohol-related morbidity later in life.

Gender-based violence and harassment at work and health and occupational outcomes. A systematic review of prospective studies.

BACKGROUND: Many people experience forms of gender-based violence and harassment (GBVH) in the context of their work. This includes a wide range of experiences, from subtle expressions of hostility to physical assault, that can also be of a sexual nature (e.g., sexual harassment or assault). This systematic review aimed to summarize findings about the prospective associations of work-related GBVH with people's health and occupational situation. METHODS: We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Scopus, Web of Science, MEDLINE and PsycINFO were searched for prospective studies in English from 1990 to May 24, 2023. Studies were included if they concerned a working population, exposure to any form of GBVH in the work context, and a health outcome or manifest occupational outcome. Quality was assessed with a modified version of the Cochrane 'Tool to Assess Risk of Bias in Cohort Studies', and studies assessed as low quality were excluded from the narrative synthesis. For the narrative synthesis, we grouped the results by similar exposures and outcomes and reported the strength and statistical significance of the associations. RESULTS: Of the 1 937 screened records, 29 studies were included in the narrative synthesis. Studies were mainly conducted in the USA and northern Europe and investigated exposure to sexual violence or harassment (SVH). Only two included studies investigated non-sexual kinds of GBVH. Consistently, studies showed associations of work-related SVH with poor mental health and there were indications of an association with hazardous substance use. There was no consistent evidence for an association of SVH with subsequent sickness absence, and there were too few studies concerning physical health and occupational outcomes to synthesize the results. CONCLUSIONS: There is consistent evidence of work-related SVH as a risk factor for subsequent poor mental health. There is no indication that the health consequences of SVH differ between women and men, although women are more often affected. There is a need for conceptual consistency, the consideration of non-sexual behaviors and prospective studies that test clear hypotheses about the temporal sequence of events.

Effects of a multi-component alcohol prevention program in the workplace on hazardous alcohol use among employees.

BACKGROUND: The workplace can be affected negatively by hazardous alcohol use, and intervening at an early stage remains a challenge. Recently, a multi-component alcohol prevention program, Alcohol Policy and Managers' skills Training (hereafter, 'APMaT'), was delivered at the organizational level. In a previous outcome evaluation, APMaT appeared to be effective at the managerial level. The current study takes a step further by aiming to evaluate the effectiveness of APMaT in decreasing the alcohol risk level among employees. METHODS: Data from 853 employees (control: n = 586; intervention: n = 267) were gathered through a cluster-randomized study. To analyze changes in the odds of hazardous alcohol use among employees, multilevel logistic regression was applied using group (control vs. intervention), time (baseline vs. 12-month follow-up), and the multiplicative interaction term (group × time) as the main predictors. The intervention effect was further adjusted for sociodemographic characteristics and policy awareness. RESULTS: No statistically significant difference was observed in the odds of hazardous alcohol use, although employees in the intervention group showed a larger decrease compared to the control group. This remained even after adjusting for several factors, including the sociodemographic factors and policy awareness. CONCLUSIONS: The findings are insufficient to determine the effectiveness of APMaT at the employee level at the current stage of the evaluation. Future studies should strive to identify issues with implementation processes in workplace-based alcohol interventions. TRIAL REGISTRATION: The trial was retrospectively registered on 11/10/2019; ISCRTN ID: ISRCTN17250048.

Structural barriers to knowledge transfer and exchange among men and women in low-, middle- and high-income countries: an international cross-sectional study with vaccine researchers in 44 countries.

BACKGROUND: Globally, women constitute 30% of researchers. Despite an increasing proportion of women in research, they are still less likely to have international collaborations. Literature on barriers to knowledge transfer and exchange (KTE) between men and women remains limited. This study aimed to assess perceived gender barriers to KTE activities in vaccination-related research in low-, middle- and high-income countries. METHODS: This was a cross-sectional data assessment from a self-administered questionnaire distributed to researchers in the field of vaccination research. The administered questionnaire was developed and validated by WHO and McMaster University. Descriptive statistics were carried out. Structural factors of KTE were assessed using 12 statements measured with a five-point Likert scale, ranging from 1 (strongly disagree) to 5 (strongly agree). An index ranging from 12 to 60 points was created to assess structural factors of KTE, with higher score indicating fewer perceived barriers. Multivariable linear regression modelling was applied to examine the association between KTE barriers and gender. RESULTS: A total of 158 researchers were included in the analysis. Regardless of gender and country of affiliation, researchers experienced challenges with respect to KTE activities; particularly factors related to the availability of human and financial resources and level of technical expertise among their target audience. We were also able to identify perceived facilitators among men and women, such as the presence of structures that link researchers and target audiences, the investment of target audiences in KTE efforts and the presence of stable contacts among target audiences. Our linear regression analysis showed that women perceived more barriers than men (R2 = 0.014; B = -1.069; 95% CI -4.035; 1.897). CONCLUSIONS: Men and women shared common perspectives on barriers to KTE. KTE activities could be strengthened by improving structural efforts to reduce gender differences and increase collaborations between researchers and their target audience.

Evaluation of a workplace alcohol prevention program targeted on managers' inclination to initiate early alcohol intervention.

BACKGROUND: Alcohol interventions targeting the adult population are often conducted in healthcare settings, while preventive interventions often target adolescents or young adults. The general working population is often overlooked. A workplace-based intervention, consisting of development and implementation of an organizational alcohol policy, and skills development training for managers (APMaT) was carried out in order to prevent and reduce alcohol-related harms by identifying hazardous consumers at an early stage. OBJECTIVE: This study aims to evaluate APMaT by focusing on managers' inclination to initiate early alcohol intervention. METHODS: In a cluster randomized design, data were obtained from 187 managers (control: n = 70; intervention: n = 117). Inclination to initiate early alcohol intervention was measured using three items on a 5-point Likert scale ranging from 1 (strongly disagree) to 5 (strongly agree). Changes in managers' inclination to intervene were analyzed by applying multilevel ordered logistic regression. Predictors included in the model were group (control vs. intervention), time (baseline vs. 12-month follow-up), and the multiplicative interaction term (group×time). RESULTS: Significant increase in inclination to intervene against hazardous alcohol consumption among managers in the intervention group compared to managers in the control group was observed. Specifically, a 50% increase of confidence to initiate an intervention was observed among managers in the intervention group. CONCLUSIONS: APMaT seems effective to increase managers' inclination to intervene early against hazardous consumption in the workplace. The effectiveness of APMaT at the employee level should be explored in prospective studies.

Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions.

Vascular endothelial growth factor (VEGF) stimulates angiogenesis by activating VEGF receptor-2 (VEGFR-2). The role of its homolog, placental growth factor (PlGF), remains unknown. Both VEGF and PlGF bind to VEGF receptor-1 (VEGFR-1), but it is unknown whether VEGFR-1, which exists as a soluble or a membrane-bound type, is an inert decoy or a signaling receptor for PlGF during angiogenesis. Here, we report that embryonic angiogenesis in mice was not affected by deficiency of PlGF (Pgf-/-). VEGF-B, another ligand of VEGFR-1, did not rescue development in Pgf-/- mice. However, loss of PlGF impaired angiogenesis, plasma extravasation and collateral growth during ischemia, inflammation, wound healing and cancer. Transplantation of wild-type bone marrow rescued the impaired angiogenesis and collateral growth in Pgf-/- mice, indicating that PlGF might have contributed to vessel growth in the adult by mobilizing bone-marrow-derived cells. The synergism between PlGF and VEGF was specific, as PlGF deficiency impaired the response to VEGF, but not to bFGF or histamine. VEGFR-1 was activated by PlGF, given that anti-VEGFR-1 antibodies and a Src-kinase inhibitor blocked the endothelial response to PlGF or VEGF/PlGF. By upregulating PlGF and the signaling subtype of VEGFR-1, endothelial cells amplify their responsiveness to VEGF during the 'angiogenic switch' in many pathological disorders.

Down-regulation of vascular endothelial growth factor by tissue inhibitor of metalloproteinase-2: effect on in vivo mammary tumor growth and angiogenesis.

The tissue inhibitor of metalloproteinases-2 (TIMP-2) has at least two independent functions, i.e., regulation of matrix metalloproteinases and growth promoting activity. We investigated the effects of TIMP-2 overexpression, induced by retroviral mediated gene transfer, on the in vivo development of mammary tumors in syngeneic mice inoculated with EF43.fgf-4 cells. The EF43.fgf-4 cells established by stably infecting the normal mouse mammary EF43 cells with a retroviral expression vector for the fgf-4 oncogene, are highly tumorigenic and overproduce vascular endothelial growth factor (VEGF). Despite a promotion of the in vitro growth rate of EF43.fgf-4 cells overexpressing timp-2, the in vivo tumor growth was delayed. At day 17 post-cell injection, the volume of tumor derived from TIMP-2-overexpressing cells was reduced by 80% as compared with that obtained with control cells. Overexpression of TIMP-2 was associated with a down-regulation of VEGF expression in vitro and in vivo, a reduction of vessel size, density, and blood supply in the induced tumors. In addition, TIMP-2 completely inhibited the angiogenic activity of EF43.fgf-4 cell-conditioned medium in vitro using a rat aortic ring model. Our findings suggest that overexpression of TIMP-2 delays growth and angiogenesis of mammary carcinoma in vivo and that down-regulation of VEGF expression may play an important role in this TIMP-2-mediated antitumoral and antiangiogenic effects. Finally the in vivo delivery of TIMP-2, as assessed by i.v. injection of recombinant adenoviruses vectors, significantly reduced the growth of the EF43.fgf-4-induced tumors. This effect of TIMP-2 was shown to be equally comparable with that of angiostatin, a known potent inhibitor of angiogenesis.

MT1-MMP expression promotes tumor growth and angiogenesis through an up-regulation of vascular endothelial growth factor expression.

Membrane type 1 metalloprotease (MT1-MMP) is a transmembrane metalloprotease that plays a major role in the extracellular matrix remodeling, directly by degrading several of its components and indirectly by activating pro-MMP2. We investigated the effects of MT1-MMP overexpression on in vitro and in vivo properties of human breast adenocarcinoma MCF7 cells, which do not express MT1-MMP or MMP-2. MT1-MMP and MMP-2 cDNAs were either transfected alone or cotransfected. All clones overexpressing MT1-MMP 1) were able to activate endogenous or exogenous pro-MMP-2, 2) displayed an enhanced in vitro invasiveness through matrigel-coated filters independent of MMP-2 transfection, 3) induced the rapid development of highly vascularized tumors when injected subcutaneously in nude mice, and 4) promoted blood vessels sprouting in the rat aortic ring assay. These effects were observed in all clones overexpressing MT1-MMP regardless of MMP-2 expression levels, suggesting that the production of MMP-2 by tumor cells themselves does not play a critical role in these events. The angiogenic phenotype of MT1-MMP-producing cells was associated with an up-regulation of VEGF expression. These results emphasize the importance of MT1-MMP during tumor angiogenesis and open new opportunities for the development of anti-angiogenic strategies combining inhibitors of MT1-MMP and VEGF antagonists.

Evidence for distinct regulation processes in the aclacinomycin- and doxorubicin-mediated differentiation of human erythroleukemic cells.

Human erythroleukemic K 562 cells were induced to were induced to differentiate along the erythroid lineage by anthracycline antitumor drugs, such as aclacinomycin (ACLA) and doxorubicin (DOX). Subsequent stimulation of heme and globin synthesis led to a differential quantitative expression of hemoglobins. Gower 1 (epsilon2, zeta2) was the major type for ACLA and X (epsilon2, gamma2) for DOX. Although ACLA and DOX increased both the expression of gamma-globin and porphobilinogen deaminase mRNAs, striking differences were observed in the expression of erythropoietin receptor mRNAs and in erythroid transcription factors GATA-1 and NF-E2, known to play a key role in erythroid gene regulation. Indeed, ACLA induces an increase either in the binding capacity of GATA-1 and NF-E2 or in the accumulation of erythropoietin receptor, GATA-1 and NF-E2 transcripts. In contrast, their expression with DOX was not significantly modified compared to uninduced cells, except for a slight decrease in NF-E2 expression on day 3. In conclusion, these data show that: 1. increased expression of erythroid transcription factors and erythroid genes are associated only with ACLA treatment, and 2. although cytotoxicity of both ACLA and DOX is certainly dependent on DNA intercalation, regulation of differentiation processes by these two drugs involves distinct mechanisms.

P53 protein expression in human multidrug-resistant CEM lymphoblasts.

A role for p53 in the regulation of multidrug-resistance (MDR) has been postulated as wild-type p53 suppresses and mutant p53 specifically activates the mdr1 promoter. Moreover, changes in p53 expression and/or functions could be implicated in drug resistance. As the parental lymphoblastic CCRF-CEM cell line has been described as expressing a mutated form of p53, we have examined p53 and mdm2 protein levels in the human multidrug-resistant CEM-VLB cell line variant. These drug-resistant CEM-VLB cells, which have increased expressions of mdr1 and P-glycoprotein, displayed p53 and mdm2 protein expressions similar to those observed in their sensitive CCRF-CEM counterparts. Treatment of these drug-resistant cells with non-toxic doses of the resistance-inducing drug vinblastin induced a strong increase in p53 protein and mRNA but was ineffective on mdm2 protein expression, or mdr1 mRNA expression. These data indicate that mutant p53 protein was not overexpressed in these MDR cells. This overexpression could be induced by microtubule-active drug treatment, but, as previously observed in other sensitive cell lines, mutant p53 from these MDR cells was unable to positively regulate mdm2 gene product expression.

Anthracyclines as tumor cell differentiating agents: effects on the regulation of erythroid gene expression.

Tumor cells, and particularly leukemic cells, can be considered as maturation-arrested cells which have escaped some normal control and continue to proliferate. This maturation arrest can be reversed by differentiation agents such as antitumor drugs currently used in conventional cytotoxic chemotherapy. In this respect, anthracyclines have been shown to trigger the differentiation of leukemic and solid tumor cells, but the molecular mechanisms by which such drugs lead to the differentiating phenotype are still poorly understood. Using human leukemic multipotent K562 cells, we have demonstrated that subtoxic concentrations of aclacinomycin (ACLA) and doxorubicin (DOX) preferentially stimulate the hemoglobinic pathway (globins and heme synthesis) and the expression of mRNAs of globins and of porphobilinogen deaminase (PBGD). However, our results indicate that both drugs exert this differentiating effect along distinct regulatory pathways. Indeed, only ACLA and not DOX induces the expression of erythropoietin receptor (EpoR) mRNAs and of membrane EpoR, as well as an overexpression of the erythroid transcription factors GATA-1 and NF-E2 known to play a central role in erythroid gene regulation. Similarly, using transfection assays, ACLA but not DOX activates the regulatory regions (promoters and enhancers) of GATA-1, EpoR, PBGD, epsilon- and gamma-globin genes. Finally, results of run-on assays indicate that ACLA induces an enhancement of the transcription rate of these erythroid genes whereas DOX preferentially increases stability of GATA-1, NF-E2 and PBGD mRNAs. In conclusion, ACLA mainly acts at the transcriptional level via specific activation of erythroid regulatory regions whereas DOX rather acts at the posttranscriptional level by increasing the half-lives of erythroid mRNAs.

New functions of stromal proteases and their inhibitors in tumor progression.

Acquisition of invasive metastatic potential through protease expression is a key event in tumor progression. In carcinomas, the production of metalloproteinases and serine proteinases is regulated by a cross talk between stromal cells and cancer cells. Paradoxically, high rather than low levels of their inhibitors predict poor survival of patients suffering from a variety of cancers. Recent observations suggest a much more complex role of these inhibitors in tumor progression than expected initially.

[Role of plasminogen activator inhibitor type 1 in tumor angiogenesis]. / Rôle de l'inhibiteur des activateurs de plasminogène de type 1 dans l'angiogénèse tumorale.

The plasminogen/plasmin system plays a key role in cancer progression, presumably via mediating extracellular matrix degradation and tumour cell migration. High levels of components of the plasminogen activation system, and paradoxically also its inhibitor, plasminogen activator inhibitor 1 (PAI-1), have been correlated with a poor prognosis for patients with cancers of different types. Recent findings clearly suggest that PAI-1 is essential for capillary sprouting during tumour angiogenesis. Moreover, there is accumulating evidence that both the urokinase receptor and PAI-1 are multifunctional proteins involved not only in extracellular matrix proteolysis but also in cellular adhesion and migration through their binding site for vitronectin. The understanding of whether PAI-1 plays a regulatory role in angiogenesis by tightly controlling proteolytic activity or by influencing cell migration could allow a new anti-angiogenic approach for tumour therapy.

Improved quantification of angiogenesis in the rat aortic ring assay.

In vitro angiogenesis assays are essential for the identification of potential angiogenic agents and screening for pharmacological inhibitors. Among these assays, the rat aortic ring model developed by Nicosia bridges the gap between in vivo and in vitro models. The quantification of angiogenesis on this system must be applicable to characterise vascular networks of various states of complexity. We present here an improved computer-assisted image analysis which allows: (1) the determination of the aortic ring area and its factor shape; (2) the number of microvessels, the total number of branchings, the maximal microvessel length and the microvessel distribution; (3) the total number of isolated fibroblast-like cells and their distribution. We show that this method is suitable to quantify spontaneous angiogenesis as well as to analyse a complex microvascular network induced by various concentrations of vascular endothelial growth factor (VEGF). In addition, by evaluating a new parameter, the fibroblast-like cell distribution, our results show that: (1) during spontaneous angiogenic response, maximal fibroblast-like cell migration delimits microvascular outgrowth; and (2) the known angiogenic inhibitor Batimastat prevents endothelial cell sprouting without completely blocking fibroblast-like cell migration. Finally, this new method of quantification is of great interest to better understand angiogenesis and to test pro- or anti-angiogenic agents.

Production and activation of matrix metalloprotease-9 (MMP-9) by HL-60 promyelocytic leukemia cells.

Human promyelocytic HL-60 cells have been used as a model of acute leukemia to investigate the expression and the regulation of matrix metalloproteases (MMPs), known to contribute to the degradation of extracellular matrix components. As shown by gelatin zymography, HL-60 cells constitutively released significant amounts of proMMP-9 (92 kDa) and moderate amounts of proMMP-2 (72 kDa). Furthermore, casein zymography confirmed the presence of serine proteases in the form of pro-urokinase. Activation of proMMP-9 was dependent on the plasminogen activator/plasmin (PA/plasmin) system and was inhibited by aprotinin. MMP-9 was only detected in cellular extracts or conditioned media incubated with HL-60 cells, indicating that cells are essential to the activation process. Addition of plasminogen increased by 3-fold the basal invasive rate of these cells across a matrigel layer (2.1% versus 0.7% in control cells after 4 h of incubation). Taken together, these results indicate that HL-60 cells exhibit an autocrine activation mechanism of proMMP-9 via the PA/plasmin system and that activation of proMMP-9 increases their invasive potential.

Induction of endothelial cell apoptosis by solid tumor cells.

The mechanisms by which tumor cells extravasate to form metastasis remain controversial. Previous studies performed in vivo and in vitro demonstrate that the contact between tumor cells and the vascular wall impairs endothelium integrity. Here, we investigated the effect of breast adenocarcinoma MCF-7 cells on the apoptosis of human umbilical vein endothelial cells (HUVEC). TUNEL labeling, nuclear morphology, and DNA electrophoresis indicated that MCF-7 cells induced a two- to fourfold increase in HUVEC apoptosis. Caspase-3 activity was significantly enhanced. Neither normal cells tested (mammary epithelial cells, fibroblasts, leukocytes) nor transformed hematopoietic cells tested (HL60, Jurkat) induced HUVEC apoptosis. On the contrary, cells derived from solid tumors (breast adenocarcinoma, MDA-MB-231 and T47D; fibrosarcoma, HT 1080) had an effect similar to that of MCF-7 cells. The induction of apoptosis requires cell-to-cell contact, since it could not be reproduced by media conditioned by MCF-7 cells cultured alone or cocultured with HUVEC. Our results suggest that cells derived from solid tumors may alter the endothelium integrity by inducing endothelial cell apoptosis. On the contrary, normal or malignant leukocytes appear to extravasate by distinct mechanisms and do not damage the endothelium. Our data may lead to a better understanding of the steps involved in tumor cell extravasation.

Emerging roles for proteinases in cancer.

Metalloproteinases and serine proteinases have been associated with tumor invasion and formation of metastasis which represent the major obstacles to cancer cure. The contribution of proteinases in these processes was initially thought to be the destruction of extracellular matrices. However, recent evidence suggests that they mainly affect tumor growth rather than invasion. Proteinases can indeed generate active matrix protein fragments, influence the release, the activation and the bioavailability of growth factors, and consequently modulate tumor cell growth, apoptosis and angiogenesis. Additionally, proteinases, their receptors and/or inhibitors can be directly involved in cell migration and in the processing or shedding of cell surface proteins. Further elucidation of the functions of proteinases is essential for the development of novel anticancer strategies.

Murine 5T multiple myeloma cells induce angiogenesis in vitro and in vivo.

Multiple myeloma is a B cell malignancy. Recently, it has been demonstrated that bone marrow samples of patients with multiple myeloma display an enhanced angiogenesis. The mechanisms involved seem to be multiple and complex. We here demonstrate that the murine 5T multiple myeloma models are able to induce angiogenesis in vitro by using a rat aortic ring assay and in vivo by determining the microvessel density. The rat aortic rings cultured in 5T multiple myeloma conditioned medium exhibit a higher number of longer and more branched microvessels than the rings cultured in control medium. In bone marrow samples from 5T multiple myeloma diseased mice, a statistically significant increase of the microvessel density was observed when compared to bone marrow samples from age-matched controls. The angiogenic phenotype of both 5T multiple myeloma cells could be related, at least in part, to their capacity to produce vascular endothelial growth factor. These data clearly demonstrate that the 5T multiple myeloma models are good models to study angiogenesis in multiple myeloma and will allow to unravel the mechanisms of neovascularisation, as well as to test new putative inhibitors of angiogenesis.

Role of plasminogen activator-plasmin system in tumor angiogenesis.

New blood formation or angiogenesis has become a key target in therapeutic strategies aimed at inhibiting tumor growth and other diseases associated with neovascularization. Angiogenesis is associated with important extracellular remodeling involving different proteolytic systems among which the plasminogen system plays an essential role. It belongs to the large serine proteinase family and can act directly or indirectly by activating matrix metalloproteinases or by liberating growth factors and cytokines sequestered within the extracellular matrix. Migration of endothelial cells is associated with significant upregulation of proteolysis and, conversely, immunoneutralization or chemical inhibition of the system reduces angiogenesis in vitro. On the other hand, genetically altered mice developed normally without overt vascular anomalies indicating the possibility of compensation by other proteases in vivo. Nevertheless, they have in some experimental settings revealed unanticipated roles for previously characterized proteinases or their inhibitors. In this review, the complex mechanisms of action of the serine proteases in pathological angiogenesis are summarized alongside possible therapeutic applications.