Pin1 plays a key role in the response to treatment and clinical outcome in triple negative breast cancer

Background: Triple negative breast cancer (TNBC) is the subset of breast cancer associated with the poorest outcome, and currently lacks targeted treatments. Standard of care (SoC) chemotherapy often consists of DNA damaging chemotherapies ± taxanes, with a range of responses observed. However, we currently lack biomarkers to predict this response and lack alternate treatment options. Methods: Pin1 expression was modulated in vitro and proliferation and treatment response was studied. Pin1 expression was analysed in patient samples and correlated with clinical outcome. Results: In this study, we have shown that the prolyl isomerase, Pin1, which is highly expressed in TNBC, plays a key role in pathogenesis of the disease. Knockdown of Pin1 in TNBC resulted in cell death while the opposite is seen in normal cells. We revealed for the first time that loss of Pin1 leads to increased sensitivity to Taxol but only in the absence of functional BRCA1. Conversely, loss of Pin1 results in decreased sensitivity to DNA-damaging agents independent of BRCA1 status. Analysis of Pin1 gene or IHC-based expression in over 200 TNBC patient samples revealed a novel role for Pin1 as a TNBC-specific biomarker, with high expression associated with improved outcome in the context of SoC chemotherapy. Preliminary data indicated this may be extended to other treatment options (e.g. Cisplatin/Parp Inhibitors) that are gaining traction for the treatment of TNBC. Conclusions: This study highlights the important role played by Pin1 in TNBC and highlights the context-dependent functions in modulating cell growth and response to treatment

Activation of STING-Dependent Innate Immune Signaling By S-Phase-Specific DNA Damage in Breast Cancer

Background: Previously we identified a DNA damage response–deficient (DDRD) molecular subtype within breast cancer. A 44-gene assay identifying this subtype was validated as predicting benefit from DNA-damaging chemotherapy. This subtype was defined by interferon signaling. In this study, we address the mechanism of this immune response and its possible clinical significance. Methods: We used immunohistochemistry (IHC) to characterize immune infiltration in 184 breast cancer samples, of which 65 were within the DDRD subtype. Isogenic cell lines, which represent DDRD-positive and -negative, were used to study the effects of chemokine release on peripheral blood mononuclear cell (PBMC) migration and the mechanism of immune signaling activation. Finally, we studied the association between the DDRD subtype and expression of the immune-checkpoint protein PD-L1 as detected by IHC. All statistical tests were two-sided. Results: We found that DDRD breast tumors were associated with CD4+ and CD8+ lymphocytic infiltration (Fisher’s exact test P < .001) and that DDRD cells expressed the chemokines CXCL10 and CCL5 3.5- to 11.9-fold more than DNA damage response–proficient cells (P < .01). Conditioned medium from DDRD cells statistically significantly attracted PBMCs when compared with medium from DNA damage response–proficient cells (P < .05), and this was dependent on CXCL10 and CCL5. DDRD cells demonstrated increased cytosolic DNA and constitutive activation of the viral response cGAS/STING/TBK1/IRF3 pathway. Importantly, this pathway was activated in a cell cycle–specific manner. Finally, we demonstrated that S-phase DNA damage activated expression of PD-L1 in a STING-dependent manner. Conclusions: We propose a novel mechanism of immune infiltration in DDRD tumors, independent of neoantigen production. Activation of this pathway and associated PD-L1 expression may explain the paradoxical lack of T-cell-mediated cytotoxicity observed in DDRD tumors. We provide a rationale for exploration of DDRD in the stratification of patients for immune checkpoint–based therapies

A Neurodisparity Index of Nationwide Access to Neurological Health Care in Northern Ireland.

Nationwide disparities in managing neurological patients have rarely been reported. We compared neurological health care between the population who reside in a Health and Social Care Trust with a tertiary neuroscience center and those living in the four non-tertiary center Trusts in Northern Ireland. Using the tertiary center Trust population as reference, neurodisparity indices (NDIs) defined as the number of treated patients resident in each Trust per 100,000 residents compared to the same ratio in the tertiary center Trust for a fixed time period. NDIs were calculated for four neurological pathways-intravenous thrombolysis (iv-tPA) and mechanical thrombectomy (MT) for acute ischemic stroke (AIS), disease modifying treatment (DMT) in multiple sclerosis (MS) and admissions to a tertiary neurology ward. Neurological management was recorded in 3,026 patients. Patients resident in the tertiary center Trust were more likely to receive AIS treatments (iv-tPA and MT) and access to the neurology ward (p < 0.001) than patients residing in other Trusts. DMT use for patients with MS was higher in two non-tertiary center Trusts than in the tertiary center Trust. There was a geographical gradient for MT for AIS patients and ward admissions. Averaged NDIs for non-tertiary center Trusts were: 0.48 (95%CI 0.32-0.71) for patient admissions to the tertiary neurology ward, 0.50 (95%CI 0.38-0.66) for MT in AIS patients, 0.78 (95%CI 0.67-0.92) for iv-tPA in AIS patients, and 1.11 (95%CI 0.99-1.26) for DMT use in MS patients. There are important neurodisparities in Northern Ireland, particularly for MT and tertiary ward admissions. Neurologists and health service planners should be aware that geography and time-dependent management of neurological patients worsen neurodisparities

A Neurodisparity Index of Nationwide Access to Neurological Health Care in Northern Ireland

Nationwide disparities in managing neurological patients have rarely been reported. We compared neurological health care between the population who reside in a Health and Social Care Trust with a tertiary neuroscience center and those living in the four non-tertiary center Trusts in Northern Ireland. Using the tertiary center Trust population as reference, neurodisparity indices (NDIs) defined as the number of treated patients resident in each Trust per 100,000 residents compared to the same ratio in the tertiary center Trust for a fixed time period. NDIs were calculated for four neurological pathways—intravenous thrombolysis (iv-tPA) and mechanical thrombectomy (MT) for acute ischemic stroke (AIS), disease modifying treatment (DMT) in multiple sclerosis (MS) and admissions to a tertiary neurology ward. Neurological management was recorded in 3,026 patients. Patients resident in the tertiary center Trust were more likely to receive AIS treatments (iv-tPA and MT) and access to the neurology ward (p < 0.001) than patients residing in other Trusts. DMT use for patients with MS was higher in two non-tertiary center Trusts than in the tertiary center Trust. There was a geographical gradient for MT for AIS patients and ward admissions. Averaged NDIs for non-tertiary center Trusts were: 0.48 (95%CI 0.32–0.71) for patient admissions to the tertiary neurology ward, 0.50 (95%CI 0.38–0.66) for MT in AIS patients, 0.78 (95%CI 0.67–0.92) for iv-tPA in AIS patients, and 1.11 (95%CI 0.99–1.26) for DMT use in MS patients. There are important neurodisparities in Northern Ireland, particularly for MT and tertiary ward admissions. Neurologists and health service planners should be aware that geography and time-dependent management of neurological patients worsen neurodisparities

BRCA1 Regulates the Interferon γ-mediated Apoptotic Response

BRCA1 is a tumor suppressor gene implicated in transcriptional regulation. We have generated cell lines with inducible expression of BRCA1 as a tool to identify downstream targets that may be important mediators of BRCA1 function. Oligonucleotide array-based expression profiling identified 11 previously described interferon regulated genes that were up-regulated following inducible expression of BRCA1. Northern blot analysis revealed that a subset of the identified targets including IRF-7, MxA, and ISG-54 were synergistically up-regulated by BRCA1 in the presence of interferon gamma (IFN-gamma) but not interferons alpha or beta. Importantly, IFN-gamma-mediated induction of IRF-7 and MxA was attenuated in the BRCA1 mutant cell line HCC1937, an effect that was rescued following reconstitution of exogenous wild type BRCA1 in these cells. Furthermore, reconstituted BRCA1 sensitized HCC1937 cells to IFN-gamma-induced apoptotic cell death. This study identifies BRCA1 as a component of the IFN-gamma-regulated signaling pathway and suggests that BRCA1 may play a role in the regulation of IFN-gamma-mediated apoptosis

Linking the sectoral employment structure and household poverty in the United Kingdom

Structural changes in the labour markets of developed economies, and changes in their institutional characteristics, have led to growing unease about the nature of low-paid employment. Related concerns have been expressed about the persistence of low-pay, the fragmentation of work and the growth of under-employment. While all these factors have potential implications for individuals’ earnings, less is known about the connection between labour market change, patterns of sectoral growth and decline and household poverty outcomes. This article shows distinct patterns of poverty outcomes by sector of employment, after controlling for other factors. However, household characteristics, in particular the presence of a second earner, do strongly mitigate the poverty risk. Overall, the findings demonstrate that policymakers need to develop a coherent policy towards poverty that recognises the nature of jobs growth and the distribution of ‘good jobs’ across households

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

Motivational determinants among physicians in Lahore, Pakistan

Introduction: Human resource crises in developing countries have been identified as a critical aspect of poor quality and low accessibility in health care. Worker motivation is an important facet of this issue. Specifically, motivation among physicians, who are an important bridge between health systems and patients, should be considered. This study aimed to identify the determinants of job motivation among physicians, a neglected perspective, especially in developing countries. Methods: A stratified random sample of 360 physicians was selected from public primary, public secondary and public and private tertiary health facilities in the Lahore district, Pakistan. Pretested, semi-structured, self-administered questionnaires were used. For the descriptive part of this study, physicians were asked to report their 5 most important work motivators and demotivators within the context of their current jobs and in general. Responses were coded according to emergent themes and frequencies calculated. Of the 30 factors identified, 10 were classified as intrinsic, 16 as organizational and 4 as socio-cultural. Results: Intrinsic and socio-cultural factors like serving people, respect and career growth were important motivators. Conversely, demotivators across setups were mostly organizational, especially in current jobs. Among these, less pay was reported the most frequently. Fewer opportunities for higher qualifications was a demotivator among primary and secondary physicians. Less personal safety and poor working conditions were important in the public sector, particularly among female physicians. Among private tertiary physicians financial incentives other than pay and good working conditions were motivators in current jobs. Socio-cultural and intrinsic factors like less personal and social time and the inability to financially support oneself and family were more important among male physicians. Conclusion: Motivational determinants differed across different levels of care, sectors and genders. Nonetheless, the important motivators across setups in this study were mostly intrinsic and socio-cultural, which are difficult to affect while the demotivators were largely organizational. Many can be addressed even at the facility level such as less personal safety and poor working conditions. Thus, in resource limited settings a good strategic starting point could be small scale changes that may markedly improve physicians' motivation and subsequently the quality of health care

Leveraging human capital to reduce maternal mortality in India: enhanced public health system or public-private partnership?

Developing countries are currently struggling to achieve the Millennium Development Goal Five of reducing maternal mortality by three quarters between 1990 and 2015. Many health systems are facing acute shortages of health workers needed to provide improved prenatal care, skilled birth attendance and emergency obstetric services – interventions crucial to reducing maternal death. The World Health Organization estimates a current deficit of almost 2.4 million doctors, nurses and midwives. Complicating matters further, health workforces are typically concentrated in large cities, while maternal mortality is generally higher in rural areas. Additionally, health care systems are faced with shortages of specialists such as anaesthesiologists, surgeons and obstetricians; a maldistribution of health care infrastructure; and imbalances between the public and private health care sectors. Increasingly, policy-makers have been turning to human resource strategies to cope with staff shortages. These include enhancement of existing work roles; substitution of one type of worker for another; delegation of functions up or down the traditional role ladder; innovation in designing new jobs;transfer or relocation of particular roles or services from one health care sector to another. Innovations have been funded through state investment, public-private partnerships and collaborations with nongovernmental organizations and quasi-governmental organizations such as the World Bank. This paper focuses on how two large health systems in India – Gujarat and Tamil Nadu – have successfully applied human resources strategies in uniquely different contexts to the challenges of achieving Millennium Development Goal Five

P-cadherin expression in breast cancer: a review

P-cadherin is frequently over-expressed in high-grade invasive breast carcinomas and has been reported to be an enhancer of migration and invasion of breast cancer cells, being correlated with tumour aggressiveness. In addition, expression of P-cadherin is well established as an indicator of poor prognosis in human breast cancer, which has stimulated our interest in studying its role in this setting. This review describes the most important findings on P-cadherin expression and function in normal mammary tissue and breast cancer cells, emphasizing that further research is required to elucidate the role played by this protein in human mammary tumours