An extracellular matrix stiffness-induced breast cancer cell transcriptome resembles the transition from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC).

Identifying mechanisms driving the transition from ductal carcinoma in situ (DCIS) to invasive breast cancer remains a challenge in breast cancer research. Breast cancer progression is accompanied by remodelling and stiffening of the extracellular matrix, leading to increased proliferation, survival, and migration. Here, we studied stiffness-dependent phenotypes in MCF10CA1a (CA1a) breast cancer cells cultured on hydrogels with stiffness corresponding to normal breast and breast cancer. This revealed a stiffness-associated morphology consistent with acquisition of an invasive phenotype in breast cancer cells. Surprisingly, this strong phenotypic switch was accompanied by relatively modest transcriptome-wide alterations in mRNA levels, as independently quantified using both DNA-microarrays and bulk RNA sequencing. Strikingly, however, the stiffness-dependent alterations in mRNA levels overlapped with those contrasting ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC). This supports a role of matrix stiffness in driving the pre-invasive to invasive transition and suggests that mechanosignalling may be a target for prevention of invasive breast cancer.

Cell to extracellular matrix interactions and their reciprocal nature in cancer.

Interactions between the cell and the extracellular matrix (ECM) are critical in controlling the fate and behaviour of cancer cells. Alterations in either the ECM or in cellular events affect this interaction. In this mini-review we give an overview of the role of cell-ECM interactions in cancer, with a particular focus on the reciprocal nature of the cell-ECM interactions and how this contributes to cancer progression.

Regulation of protein synthesis and stability by mechanical cues and its implications in cancer.

Elevated tissue stiffness is a common feature of many solid tumors and the downstream mechanical signaling affects many cellular processes and contributes to cancer progression. Significant progress has been made in understanding how the mechanical properties of the matrix affect cancer cell behavior as well as transcription. However, how the same mechanical cues impact protein synthesis and stability and how this may contribute to disease is less well understood. Here, we present emerging evidence that cancer progression is frequently supported by gene regulation acting beyond the mRNA level and highlight some of the known crosstalk between this type of regulation and mechanotransduction in cancer as well as in other contexts. We suggest that future systematic approaches to define mechanosensitive translatomes and proteomes and how these are controlled may provide novel targets for cancer therapy.

Reticular adhesions are a distinct class of cell-matrix adhesions that mediate attachment during mitosis.

Adhesion to the extracellular matrix persists during mitosis in most cell types. However, while classical adhesion complexes, such as focal adhesions, do and must disassemble to enable mitotic rounding, the mechanisms of residual mitotic cell-extracellular matrix adhesion remain undefined. Here, we identify 'reticular adhesions', a class of adhesion complex that is mediated by integrin αvß5, formed during interphase, and preserved at cell-extracellular matrix attachment sites throughout cell division. Consistent with this role, integrin ß5 depletion perturbs mitosis and disrupts spatial memory transmission between cell generations. Reticular adhesions are morphologically and dynamically distinct from classical focal adhesions. Mass spectrometry defines their unique composition, enriched in phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2)-binding proteins but lacking virtually all consensus adhesome components. Indeed, reticular adhesions are promoted by PtdIns(4,5)P2, and form independently of talin and F-actin. The distinct characteristics of reticular adhesions provide a solution to the problem of maintaining cell-extracellular matrix attachment during mitotic rounding and division.

A pilot-study of a worksite based participatory intervention program: Its acceptability and short-term effects on work climate and attitudes in human service employees.

BACKGROUND: Psychosocial factors, including job demands and poor resources, have been linked to stress, health problems, and negative job attitudes. However, worksite based interventions and programs targeting psychosocial factors may change employees' perceptions of their work climate and work attitudes. OBJECTIVE: This pilot study describes a newly developed worksite based participatory organizational intervention program that was tested in the social service sector. It is evaluated using participants' perceptions of the intervention to investigate its acceptability as a feature of feasibility and its short-term effects on work climate factors (job demands and resources) and work-related attitudes. METHODS: Forty employees of a Swedish social service unit provided self-reports before, during, and after the intervention. RESULTS: As for effects, quantitative role overload and social support decreased while turnover intention increased. Responses to an open-ended question showed that participants considered the intervention program valuable for addressing issues relating to the psychosocial work climate. CONCLUSIONS: Although the findings are preliminary, it was possible to carry out this worksite based participatory organizational program in this particular setting. Also, the preliminary findings underscore the challenges associated with designing and implementing this type of intervention program, thus adding to the methodological discussion on implementation and evaluation.

Self-estimated life situation in patients on long-term sick leave.

OBJECTIVE: To analyse the influence of long-term sick leave on patients' life situation. DESIGN AND SUBJECTS: Cross-sectional study based on 1350 individuals with a consecutive sick leave period of 12-18 months. Half were still on sick leave, half were no longer sick-listed. METHODS: A total of 862 participants answered a postal questionnaire including 24 questions on consequences of their sick leave on daily life. Results were analysed by gender, age and type of sick leave diagnosis. Associations between consequences and return to work were analysed by multiple logistic regression. RESULTS AND CONCLUSION: Negative effects of long-term sick leave were particularly related to leisure activities, sleep and psychological well-being. A reduced alcohol intake was more prevalent than increased consumption. Among individuals with psychiatric diagnoses the consequences were polarized, with few persons unaffected, while the effects were more unipolar and negative in other diagnostic groups. Women experienced positive consequences more often than men, attributed to relationships with children and partner, sleep and psychological well-being. Improved sleep was associated with return to work, particularly among older individuals. Negative consequences on life situation are far more common than positive consequences among patients on long-term sick leave. Benefits as well as adverse effects differ depending on diagnosis, age and gender.

Flexible pay but fixed expenses: personal financial strain among on-call employees.

The aim of the study was to investigate the financial circumstances of a group of temporary employees and whether personal financial strain is related to an increased risk of ill-health. The study group consisted of 778 on-call employees. The response rate to a mailed questionnaire was 56 percent. Twenty percent of respondents stated that they had experienced economic difficulties of some kind. More than 50 percent regarded their form of employment as an impediment to obtaining a loan, and approximately 40 percent regarded it as a barrier to acquiring a housing contract. The study group is strongly polarized with regard to personal financial matters. There is a clear connection between poverty and health. Individuals who were both worried about their personal finances and objectively poor had far lower levels of psychological well-being (as measured by GHQ-12), more stomach, back, and neck complaints, more headaches, and greater tiredness and listlessness. Sleep disturbances acted as a mediating variable between financial pressure and stomach problems.

Leader communication approaches and patient safety: An integrated model.

INTRODUCTION: Leader communication is known to influence a number of employee behaviors. When it comes to the relationship between leader communication and safety, the evidence is more scarce and ambiguous. The aim of the present study is to investigate whether and in what way leader communication relates to safety outcomes. The study examines two leader communication approaches: leader safety priority communication and feedback to subordinates. These approaches were assumed to affect safety outcomes via different employee behaviors. METHOD: Questionnaire data, collected from 221 employees at two hospital wards, were analyzed using structural equation modeling. RESULTS: The two examined communication approaches were both positively related to safety outcomes, although leader safety priority communication was mediated by employee compliance and feedback communication by organizational citizenship behaviors. CONCLUSION: The findings suggest that leader communication plays a vital role in improving organizational and patient safety and that different communication approaches seem to positively affect different but equally essential employee safety behaviors. PRACTICAL APPLICATIONS: The results highlights the necessity for leaders to engage in one-way communication of safety values as well as in more relational feedback communication with their subordinates in order to enhance patient safety.

Characterization and channel coupling of the P2Y(12) nucleotide receptor of brain capillary endothelial cells.

Rat brain capillary endothelial (B10) cells express an unidentified nucleotide receptor linked to adenylyl cyclase inhibition. We show that this receptor in B10 cells is identical in sequence to the P2Y(12) ADP receptor ("P2Y(T)") of platelets. When expressed heterologously, 2-methylthio-ADP (2-MeSADP; EC(50), 2 nm), ADP, and adenosine 5'-O-(2-thio)diphosphate were agonists of cAMP decrease, and 2-propylthio-D-beta,gamma-difluoromethylene-ATP was a competitive antagonist (K(B), 28 nm), as in platelets. However, 2-methylthio-ATP (2-MeSATP) (EC(50), 0.4 nm), ATP (1.9 microm), and 2-chloro-ATP (190 nm), antagonists in the platelet, were also agonists. 2-MeSADP activated (EC(50), 0.1 nm) GIRK1/GIRK2 inward rectifier K(+) channels when co-expressed with P2Y(12) receptors in sympathetic neurons. Surprisingly, P2Y(1) receptors expressed likewise gave that response; however, a full inactivation followed, absent with P2Y(12) receptors. A new P2Y(12)-mediated transduction was found, the closing of native N-type Ca(2+) channels; again both 2-MeSATP and 2-MeSADP are agonists (EC(50), 0.04 and 0.1 nm, respectively). That action, like their cAMP response, was pertussis toxin-sensitive. The Ca(2+) channel inhibition and K(+) channel activation are mediated by beta gamma subunit release from a heterotrimeric G-protein. G alpha subunit types in B10 cells were also identified. The presence in the brain capillary endothelial cell of the P2Y(12) receptor is a significant extension of its functional range.