David Scoones

Tissue-specific expression and dimerization of the endoplasmic reticulum oxidoreductase Ero1β

Endoplasmic reticulum oxidoreductases (Eros) are essential for the formation of disulfide bonds. Understanding disulfide bond catalysis in mammals is important because of the involvement of protein misfolding in conditions such as diabetes, arthritis, cancer, and aging. Mammals express two related Ero proteins, Ero1α and Ero1β. Ero1β is incompletely characterized but is of physiological interest because it is induced by the unfolded protein response. Here, we show that Ero1β can form homodimers and mixed heterodimers with Ero1α, in addition to Ero-PDI dimers. Ero-Ero dimers require the Ero active site, occur in vivo, and can be modeled onto the Ero1p crystal structure. Our data indicate that the Ero1β protein is constitutively strongly expressed in the stomach and the pancreas, but in a cell-specific fashion. In the stomach, selective expression of Ero1β occurs in the enzyme-producing chief cells. In pancreatic islets, Ero1β expression is high, but is inversely correlated with PDI and PDIp levels, demonstrating that cell-specific differences exist in the regulation of oxidative protein folding in vivo.

Variably protease-sensitive prionopathy in a PRNP codon 129 heterozygous UK patient with co-existing tau, α synuclein and Aβ pathology.

In 2008 a novel human prion disease, termed proteinasesensitive prionopathy (PSPr) was reported [2]. Affected patients had no known risk factors for prion exposure and no mutations in the prion protein gene (PRNP), but all were VV at codon 129 of PRNP [2]. Subsequently, we prospectively identified a similar case in the UK [3] and another was identified retrospectively from Holland [4]. The effect of PRNP codon 129 on the PSPr phenotype has been recently reported in a further series including six MV and three MM genotypes [6]. The authors identified genotypic effects on clinical, pathological and biochemical features and proposed renaming the condition ‘‘variably protease-sensitive prionopathy’’ (VPSPr) [6]. Neuropathological features in VPSPr include minimal spongiform change, minimal gliosis, microplaques in the cerebellum, and prion protein accumulation as coarse aggregates, granules and microplaques. However, the defining feature of VPSPr is the presence of abnormal prion protein (PrP) that is less protease-resistant than in other human prion diseases, resulting in a faint ladder of low molecular weight prion protein core fragments. We describe a second VPSPr UK patient, identified prospectively, who is MV at PRNP codon 129, with some atypical pathological features. The patient developed neurological symptoms at the age of 76 and died after 12 months. Initial symptoms were forgetfulness, a tendency to drift off the subject in conversation, and visuo-spatial perceptual problems. His MMSE was recorded as 22/30 at 2 months; at 4 months, he had walking difficulties. At 6 months, he was quiet, withdrawn, could not write his name and at 8 months his MMSE was 10/30. At 9 months, he required assistance for walking, had an action tremor in his arms and urinary

Postmortem findings in a case of variant Creutzfeldt-Jakob disease treated with intraventricular pentosan polysulfate

Background A small number of patients with variant Creutzfeldt-Jakob disease (vCJD) have been treated with intraventicular pentosan polysulfate (iPPS) and extended survival has been reported in some cases. To date, there have been no reports on the findings of postmortem examination of the brain in treated patients and the reasons for the extended survival are uncertain. We report on the neuropathological findings in a case of vCJD treated with PPS. Methods Data on survival in vCJD is available from information held at the National CJD Research and Surveillance Unit and includes the duration of illness in 176 cases of vCJD, five of which were treated with iPPS. One of these individuals, who received iPPS for 8 years and lived for 105 months, underwent postmortem examination, including neuropathological examination of the brain. Results The mean survival in vCJD is 17 months, with 40 months the maximum survival in patients not treated with PPS. In the 5 patients treated with PPS survival was 16 months, 45 months, 84 months, 105 months and 114 months. The patient who survived 105 months underwent postmortem examination which confirmed the diagnosis of vCJD and showed severe, but typical, changes, including neuronal loss, astrocytic gliosis and extensive prion protein (PrP) deposition in the brain. The patient was also given PPS for a short period by peripheral infusion and there was limited PrP immunostaining in lymphoreticular tissues such as spleen and appendix. Conclusions Treatment with iPPS did not reduce the overall neuropathological changes in the brain. The reduced peripheral immunostaining for PrP may reflect atrophy of these tissues in relation to chronic illness rather than a treatment effect. The reason for the long survival in patients treated with iPPS is unclear, but a treatment effect on the disease process cannot be excluded.

Cervical intra-/extramedullary solitary fibrous tumour.

A 53-year-old man presented with a 9-month history of symptoms of right-sided weakness, tingling and hypersentivity to clothes on both sides of the body. MRI revealed a large intraspinal intradural tumour at the level of C3–C4 in the cervical cord. The final histology was a solitary fibrous tumour (SFT) of the cervical spinal cord. The radiological diagnosis, surgical management and histology are reviewed.

Recurrent cerebral metastasis from a cardiac myxoma: case report and review of literature

We report the case of a 65-year-old patient who had complete excision of an atrial myxoma and subsequently presented to our unit with recurrent cerebral metastasis. The case demonstrates that cardiac myxoma despite benign histological appearance is capable of metastatic spread.

Expression of the Endoplasmic Reticulum Oxidoreductase Ero1α in Gastro-Intestinal Cancer Reveals a Link Between Homocysteine and Oxidative Protein Folding

AIM Ero proteins are central to oxidative protein folding in the endoplasmic reticulum (ER), but their expression varies in a tissue-specific manner. The aim of this work was to establish the expression of Ero1α in the digestive system and to examine the behavior of Ero1α in premalignant Barretts esophagus, esophageal (OE) and gastric cancers and esophageal cancer cell lines. RESULTS Ero1α is expressed in the columnar epithelium of Barretts tissue, and in OE tumors and gastric tumors. Homocysteine, a precursor in the metabolism of cysteine and methionine, induces the active Ox1 form of Ero1α in the OE cancer cell line OE33. INNOVATION These results demonstrate for the first time that Ero1α can sense the level of an amino acid precursor, identifying a potential link between diet, antioxidants, and oxidative protein folding in the ER. CONCLUSION The high expression of Ero1α in cancers of the esophagus and stomach demonstrates the importance of ER redox regulation in the gastro-intestinal (GI) tract in health and disease. Proteins and metabolites involved in disulfide bond formation and redox regulation may be suitable targets for both biomarker and drug development in GI cancer.

Prognostic value of hypoxia inducible factor 1α in esophageal squamous cell carcinoma

Hypoxia inducible factor 1α (HIF 1α) plays a major role in the pleitropic response observed secondary to hypoxic conditions in tumors. Its expression in the tumor cells has been correlated to tumor aggressiveness and prognosis in squamous cell carcinoma (SCC) of the esophagus in Far Eastern population, but limited information is available on the prognostic role of HIF 1α in SCC of esophagus in European population. This information may help in choosing appropriate therapeutic strategies and possibly developing a monoclonal antibody with therapeutic potential targeting the HIF 1α. Tumor samples from 36 patients diagnosed with SCC of the esophagus were collected. Prepared tissue sections were stained with validated and specific monoclonal antibodies for HIF 1α and the expression was correlated with the disease pattern and survival. Out of 36 patients, 17 patients showed low and 19 high expression of HIF 1α. There was no difference in the disease-free and overall survival between these two groups (P > 0.05, log rank test). Regression analysis showed that HIF 1α was not an independent prognostic factor for survival (P > 0.05). HIF 1α did not show prognostic value in SCC of the esophagus in our study on European population, in agreement with previous studies. Novel strategies on the therapeutic manipulation of HIF 1α in cancer are to be explored further and may have a role to play in improving treatment outcome.

An unusual case of ectopic prostate tissue in an intradural lipoma of the conus medullaris.

We report the first case of ectopic prostate tissue in a lipoma of the spine. Ectopic prostate tissue is well documented at a number of sites within the human body. Ectopic prostate tissue has previously been reported in the spine but usually in the context of spinal teratomas. This case is unique in that this is the first description of the presence of benign prostatic tissue in a lipoma of the conus medullaris. This is a highly unusual finding and probably reflects divergent differentiation or a malformative process.

Abscess formation within a Rathke's cleft cyst.

We report and discuss the rare case of a pituitary abscess forming within a Rathkes cleft cyst (RCC). A 66-year-old gentleman presented with visual deterioration and symptoms suggestive of hypopituitarism. The patient underwent transsphenoidal debulking of the lesion whereupon purulent material was discovered. Histological examination was suggestive of RCC together with numerous neutrophils characteristic of abscess. Microbiological culture of the material grew Staphylococcus aureus. The patient was treated for a RCC abscess and received antibiotics and endocrine replacement therapy. The patient has been followed up for 2 years without recurrence. Although uncommon, we recommend the consideration of RCC abscess as a differential diagnosis of a pituitary mass lesion as clinical presentation and radiological assessment are not specific in identifying these lesions preoperatively.

Recurrence of fourth ventricular choroid plexus papilloma with late occurrence of a spinal drop metastasis

Choroid plexus papillomas are rare tumours, which occasionally spread both intracranially and down the spinal canal. Spinal metastasis has been reported infrequently and only once many years since the initial diagnosis. This is the first reported case of late recurrence, metastasis and transformation of a benign to an atypical lesion.