Prosaposin activates the androgen receptor and potentiates resistance to endocrine treatment in breast cancer.

INTRODUCTION: HOX genes play vital roles in growth and development, however, atypical redeployment of these genes is often associated with steroidal adaptability in endocrine cancers. We previously identified HOXC11 to be an indicator of poor response to hormonal therapy in breast cancer. In this study we aimed to elucidate genes regulated by HOXC11 in the endocrine resistant setting. METHODS: RNA-sequencing paired with transcription factor motif-mapping was utilised to identify putative HOXC11 target genes in endocrine resistant breast cancer. Validation and functional evaluation of the target gene, prosaposin (PSAP), was performed in a panel of endocrine sensitive and resistant breast cancer cell lines. The clinical significance of this finding was explored in clinical cohorts at both mRNA and protein level. RESULTS: PSAP was shown to be regulated by HOXC11 in both tamoxifen and aromatase inhibitor (AI) resistant cell lines. Transcript levels of HOXC11 and PSAP correlated strongly in samples of primary breast tumours (r = 0.7692, n = 51). PSAP has previously been reported to activate androgen receptor (AR) in prostate cancer cells. In a panel of breast cancer cell lines it was shown that endocrine resistant cells exhibit innately elevated levels of AR compared to their endocrine sensitive counterparts. Here, we demonstrate that stimulation with PSAP can drive AR recruitment to a hormone response element (HRE) in AI resistant breast cancer cells. Functionally, PSAP promotes cell migration and invasion only in AI resistant cells and not in their endocrine sensitive counterparts. In a cohort of breast cancer patients (n = 34), elevated serum levels of PSAP were found to associate significantly with poor response to endocrine treatment (p = 0.04). Meta-analysis of combined PSAP and AR mRNA are indicative of poor disease-free survival in endocrine treated breast cancer patients (hazard ratio (HR): 2.2, P = 0.0003, n = 661). CONCLUSION: The HOXC11 target gene, PSAP, is an AR activator which facilitates adaptation to a more invasive phenotype in vitro. These findings have particular relevance to the development of resistance to AI therapy which is an emerging clinical issue. PSAP is a secreted biomarker which has potential in identifying patients failing to exhibit sustained response to hormonal treatment

Removal of a below knee plaster cast worn for 28 months: a case report

<p>Abstract</p> <p>Introduction</p> <p>An unusual situation in which a below knee cast was removed after 28 months is reported. To the best of our knowledge no similar cases have been reported in the literature.</p> <p>Case presentation</p> <p>The cast was removed from the leg of a 45-year-old Caucasian woman. Significant muscle atrophy and dense skin scales were present but the underlying skin surface was relatively healthy with only small pitted 1-2 mm ulcers. No pathogenic organisms were cultured from this environment.</p> <p>Conclusion</p> <p>It seems likely that skin can tolerate cast immobilization for prolonged duration.</p

Androgen secreting steroid cell tumor of the ovary in a young lactating women with acute onset of severe hyperandrogenism: a case report and review of literature

<p>Abstract</p> <p>Introduction</p> <p>Steroid cell tumors of the ovary account for less than 0.1% of all ovarian tumors <abbrgrp><abbr bid="B1">1</abbr></abbrgrp> and these tumours may present at any age in association with interesting presentations related to the hormonal activity and virilizing properties of tumor. Hayes and Scully <abbrgrp><abbr bid="B2">2</abbr></abbrgrp> reported 63 cases in patients ranging from 2 to 80 years of age. The subtype, not otherwise specified, is associated with androgenic changes in approximately one half of patients with this tumour <abbrgrp><abbr bid="B1">1</abbr></abbrgrp>. In a series of 63 cases from Massachusetts General Hospital, 94% of the tumors were found to be unilateral and 28.6% were malignant <abbrgrp><abbr bid="B3">3</abbr></abbrgrp>. As most of these tumors are diagnosed at an early stage and do not recur or metastasize, little is known about their response to therapies such as chemotherapy or radiation <abbrgrp><abbr bid="B3">3</abbr></abbrgrp>.</p> <p>Case Presentation</p> <p>We present the case of a 22-year old lactating woman who presented with four months of amenorrhea associated with signs of virilization. Clinical and diagnostic evaluation revealed a right adenexal mass and elevated serum levels of testosterone and she was diagnosed as having a stage 1A androgen secreting steroid cell tumor. In view of the early stage of the disease, she underwent right salpingo-oopherectomy. Histopathological examination and immunohistochemistry confirmed the diagnosis. Two months after surgery she regained normal menses and showed regression of the androgenic changes.</p> <p>Conclusion</p> <p>Surgery remains the mainstay of the treatment of gonadotrophin receptor positive steroid cell tumors although medical therapy using Gonadotrophin Releasing Hormone [GnRH analogues has been tried recently in recurrent or inoperable cases. There is no described effective chemotherapy or radiotherapy for this condition.</p

Developing and implementing an integrated delirium prevention system of care:a theory driven, participatory research study

Background: Delirium is a common complication for older people in hospital. Evidence suggests that delirium incidence in hospital may be reduced by about a third through a multi-component intervention targeted at known modifiable risk factors. We describe the research design and conceptual framework underpinning it that informed the development of a novel delirium prevention system of care for acute hospital wards. Particular focus of the study was on developing an implementation process aimed at embedding practice change within routine care delivery. Methods: We adopted a participatory action research approach involving staff, volunteers, and patient and carer representatives in three northern NHS Trusts in England. We employed Normalization Process Theory to explore knowledge and ward practices on delirium and delirium prevention. We established a Development Team in each Trust comprising senior and frontline staff from selected wards, and others with a potential role or interest in delirium prevention. Data collection included facilitated workshops, relevant documents/records, qualitative one-to-one interviews and focus groups with multiple stakeholders and observation of ward practices. We used grounded theory strategies in analysing and synthesising data. Results: Awareness of delirium was variable among staff with no attention on delirium prevention at any level; delirium prevention was typically neither understood nor perceived as meaningful. The busy, chaotic and challenging ward life rhythm focused primarily on diagnostics, clinical observations and treatment. Ward practices pertinent to delirium prevention were undertaken inconsistently. Staff welcomed the possibility of volunteers being engaged in delirium prevention work, but existing systems for volunteer support were viewed as a barrier. Our evolving conception of an integrated model of delirium prevention presented major implementation challenges flowing from minimal understanding of delirium prevention and securing engagement of volunteers alongside practice change. The resulting Prevention of Delirium (POD) Programme combines a multi-component delirium prevention and implementation process, incorporating systems and mechanisms to introduce and embed delirium prevention into routine ward practices. Conclusions: Although our substantive interest was in delirium prevention, the conceptual and methodological strategies pursued have implications for implementing and sustaining practice and service improvements more broadly

Re-discovery of a "living fossil" coccolithophore from the coastal waters of Japan and Croatia

The extant coccolithophore Tergestiella adriatica Kamptner, which had not been reported since its original description in 1940, was recently re-discovered in coastal-nearshore waters at Tomari, Tottori (Japan) and offshore Rovinj (Croatia). Morphological analysis shows that extant Tergestiella and the Mesozoic genus Cyclagelosphaera (Watznaueriaceae), thought to have been extinct since the early Eocene (~. 54. Ma), are virtually identical. Molecular phylogenetic study supports the inference that T. adriatica is a direct descendent of Cyclagelosphaera. It is therefore a remarkable example of a living fossil. Our documentation of patchy coastal distribution in living T. adriatica and records of rare occurrences of fossil Cyclagelosphaera in Oligocene-Miocene shallow water sediments. , from the New Jersey shelf, suggest that Tergestiella/. Cyclagelosphaera was restricted to nearshore environments during much of the Cenozoic. This restricted ecology explains the lack of fossil Tergestiella/. Cyclagelosphaera recorded in open ocean sediments deposited during the last 54. myr.Floristic study of coccolithophores in the coastal and offshore waters of Tomari over a six-year period, show that T. adriatica occurs synchronously with the unusual neritic species, Braarudosphaera bigelowii, in mid-June. The environmental factors that induce the co-occurrence of these two taxa are uncertain, and T. adriatica did not co-occur with B. bigelowii at any other sites

Tissue-Specific Requirement for the GINS Complex During Zebrafish Development

Efficient and accurate DNA replication is particularly critical in stem and progenitor cells for successful proliferation and survival. The replisome, an amalgam of protein complexes, is responsible for binding potential origins of replication, unwinding the double helix, and then synthesizing complimentary strands of DNA. According to current models, the initial steps of DNA unwinding and opening are facilitated by the CMG complex, which is composed of a GINS heterotetramer that connects Cdc45 with the mini-chromosome maintenance (Mcm) helicase. In this work, we provide evidence that in the absence of GINS function DNA replication is cell autonomously impaired, and we also show that gins1 and gins2 mutants exhibit elevated levels of apoptosis restricted to actively proliferating regions of the central nervous system (CNS). Intriguingly, our results also suggest that the rapid cell cycles during early embryonic development in zebrafish may not require the function of the canonical GINS complex as neither zygotic Gins1 nor Gins2 isoforms seem to be present during these stages

Holographic chiral magnetic spiral

We study the ground state of baryonic/axial matter at zero temperature chiral-symmetry broken phase under a large magnetic field, in the framework of holographic QCD by Sakai-Sugimoto. Our study is motivated by a recent proposal of chiral magnetic spiral phase that has been argued to be favored against previously studied phase of homogeneous distribution of axial/baryonic currents in terms of meson super-currents dictated by triangle anomalies in QCD. Our results provide an existence proof of chiral magnetic spiral in strong coupling regime via holography, at least for large axial chemical potentials, whereas we don't find the phenomenon in the case of purely baryonic chemical potential.Comment: 24 pages, 15 figure

Tissue-Specific Requirement for the GINS Complex During Zebrafish Development.

Efficient and accurate DNA replication is particularly critical in stem and progenitor cells for successful proliferation and survival. The replisome, an amalgam of protein complexes, is responsible for binding potential origins of replication, unwinding the double helix, and then synthesizing complimentary strands of DNA. According to current models, the initial steps of DNA unwinding and opening are facilitated by the CMG complex, which is composed of a GINS heterotetramer that connects Cdc45 with the mini-chromosome maintenance (Mcm) helicase. In this work, we provide evidence that in the absence of GINS function DNA replication is cell autonomously impaired, and we also show that gins1 and gins2 mutants exhibit elevated levels of apoptosis restricted to actively proliferating regions of the central nervous system (CNS). Intriguingly, our results also suggest that the rapid cell cycles during early embryonic development in zebrafish may not require the function of the canonical GINS complex as neither zygotic Gins1 nor Gins2 isoforms seem to be present during these stages

Appetite for destruction: the inhibition of glycolysis as a therapy for tuberous sclerosis complex-related tumors

The elevated metabolic requirements of cancer cells reflect their rapid growth and proliferation and are met through mutations in oncogenes and tumor suppressor genes that reprogram cellular processes. For example, in tuberous sclerosis complex (TSC)-related tumors, the loss of TSC1/2 function causes constitutive mTORC1 activity, which stimulates glycolysis, resulting in glucose addiction in vitro. In research published in Cell and Bioscience, Jiang and colleagues show that pharmacological restriction of glucose metabolism decreases tumor progression in a TSC xenograft model