CLPTM1L/CRR9 ectodomain interaction with GRP78 at the cell surface signals for survival and chemoresistance upon ER stress in pancreatic adenocarcinoma cells

Altered regulation of endoplasmic reticulum (ER) homeostasis has been implicated in many cancers and has recently become a therapeutic and chemosensitization target of interest. We have identified Cleft Lip and Palate Transmembrane 1-Like (CLPTM1L)/Cisplatin Resistance Related Protein 9 (CRR9) as an ER stress related mediator of cytoprotection in pancreatic cancer. We recently demonstrated that CLPTM1L is highly expressed in pancreatic ductal adenocarcinoma and associated with poor outcome. Furthermore, we have discovered that CLPTM1L interacts with phosphoinositol-3-kinase-alpha at the tumor cell surface and causes up-regulation of Bcl-xL and pAkt mediated survival signaling. Here, we demonstrate surface relocalization and survival signaling by CLPTM1L triggered by endoplasmic reticular (ER) stress. We demonstrate the interaction of CLPTM1L with the central ER stress survival mediator, Glucose Regulated Protein 78 (GRP78)/Binding Immunoglobulin Protein (BiP) and PI3K-alpha /p110α. This interaction and surface relocalization of CLPTM1L and GRP78 is induced by ER stress, including that caused by treatment with gemcitabine. We demonstrate that the extracellular loop of CLPTM1L is required for gemcitabine resistance and interaction with GRP78. This interaction and the chemoresistance effect conferred by this pathway is targetable with our recently developed inhibitory CLPTM1L antibodies, which may represent novel modalities of chemosensitization and treatment of pancreatic adenocarcinoma. Anchorage independent growth, GRP78-mediated chemoresistance, and Akt phosphorylation were abrogated by inhibition of CLPTM1L. These findings demonstrate a novel and potentially targetable mechanism of cytoprotection and chemoresistance in pancreatic tumors.     

Occupation and risk of oesophageal adenocarcinoma and squamous‐cell carcinoma: The Nordic Occupational Cancer Study

To assess associations between occupation and risk of oesophageal adenocarcinoma (AC) and squamous‐cell carcinoma (SCC), data from the Nordic Occupational Cancer Study, a large population‐based cohort with long‐term follow‐up, was used. The Nordic Occupational Cancer Study includes 12.9 million individuals aged 30–64 years who participated in national censuses in Finland, Iceland, Norway and Sweden in 1960–1990. Individuals were assigned to one of the 54 occupational categories, and individuals with oesophageal cancer were identified through nationwide cancer registries with follow‐up through 2005. Country‐specific standardised incidence ratios (SIRs) with 95% confidence intervals (CIs) were estimated. During follow‐up, 4,722 ACs and 14,496 SCCs were observed. Among men, increased risks of AC and SCC were observed among waiters (SIR = 2.58, 95% CI 1.41–4.32 and SIR = 3.22, 95% CI 2.30–4.38 for AC and SCC, respectively), cooks and stewards (1.72, 1.04–2.69 and 2.53, 1.94–3.25), seamen (1.52, 1.16–1.95 and 1.77, 1.53–2.05), food workers (1.51, 1.18–1.90 and 1.21, 1.03–1.42), miscellaneous construction workers (1.24, 1.04–1.48 and 1.39, 1.25–1.54) and drivers (1.16, 1.01–1.33 and 1.23, 1.13–1.34). Decreased risks of AC and SCC were observed among technical workers, physicians, teachers, religious workers and gardeners. The SIR for AC was significantly different from that for SCC in six occupational categories. Among women, increased risks among food workers and waiters and decreased risks among teachers, nurses and assistant nurses were observed for SCC only. In both sexes, increased risks were observed among waiters and food workers, and decreased risks were observed among teachers. This large cohort study indicates that the risk of oesophageal cancer varies by occupation, but not by histological type in most occupational categories.     

Measuring childhood cancer late effects: evidence of a healthy survivor effect

Introduction

Given considerable focus on health outcomes among childhood cancer survivors, we aimed to explore whether survivor bias is apparent during long-term follow-up of childhood cancer survivors.

Methods

We identified all 1-year survivors of cancer diagnosed before 20 years of age in Denmark, Finland, Iceland, and Sweden. From the general population, we randomly sampled a comparison cohort. Study individuals were followed for hospitalizations for diseases of the gastroenterological tract, endocrine system, cardiovascular system, or urinary tract from the start of the cancer registries to 2010. We estimated cumulative incidence with death as competing risk and used threshold regression to compare the hazards of the diseases of interest at ages 20, 40, 60, and 75 years.

Results

Our study included 27,007 one-year survivors of childhood cancer and 165,620 individuals from the general population. The cumulative incidence of all four outcomes was higher for childhood cancer survivors during early adulthood, but for three outcomes, the cumulative incidence was higher for the general population after age 55 years. The hazard ratios (HRs) decreased for all outcomes with increasing age, and for two of the outcomes, the hazards were higher for the general population at older ages (endocrine diseases: age-specific HRs = 3.0, 1.4, 1.0, 0.87; Cardiovascular diseases: age-specific HRs = 4.1, 1.4, 0.97, 0.84).

Conclusions

Our findings provide empirical evidence that survivor bias attenuates measures of association when comparing survivors with the general population. The design and analysis of studies among childhood cancer survivors, particularly as this population attains older ages, should account for survivor bias to avoid misinterpreting estimates of disease burden.

     

Minerals and trace elements in Icelandic dairy products and meat

The aim of this study was to update the Icelandic Food Composition Database with respect to minerals (Ca, K, Mg, Na, and P) and trace elements (Cu, Fe, Hg, Se, and Zn) in frequently consumed agricultural products and to study the seasonal and geographical variation for these elements. Five food products typical for the Icelandic food basket were analysed: whole milk, fresh cheese (skyr), firm cheese (Gouda), lamb meat and minced beef together with skimmed milk, cream and whey. Concentrations of minerals and trace elements were determined by an inductively coupled plasma mass spectrometer (ICP-MS). Seasonal and geographical variation in whole milk was found only for selenium. Concentration of selenium in meat was variable and especially low for beef (1.4–9.6 μg/100 g fresh weight). Mercury was below the detection limit of 0.3 μg/100 g except for one sample of cheese. Skyr was rich in protein, calcium and phosphorus and retains almost all selenium in the skimmed milk used for its production. Skyr whey contains more calcium, magnesium, phosphorus and zinc than cheese whey. Skyr whey is a nutritious product, almost as rich in calcium, potassium and zinc as whole milk and could be used more by the Icelandic food industry.     

Nordic biological specimen banks as basis for studies of cancer causes and control--more than 2 million sample donors, 25 million person years and 100,000 prospective cancers

The Nordic countries have a long tradition of large-scale biobanking and comprehensive, population-based health data registries linkable on unique personal identifiers, enabling follow-up studies spanning many decades. Joint Nordic biobank-based studies provide unique opportunities for longitudinal molecular epidemiological research. The purpose of the present paper is to describe the possibilities for such joint studies, by describing some of the major Nordic biobank cohorts with a standardised calculation of the cancer incidence in these cohorts. Altogether two million donors have since 1966 donated more than four million biological samples, stored at -20 degrees C to -135 degrees C, to 17 biobank cohorts in Finland, Iceland, Norway and Sweden. As a result of joint database handling principles, the accuracy of personal identifiers and completeness of follow-up for vital status in all participating biobanks was improved. Thereafter, the cancer incidence was determined using follow-up through the national cancer registries. Biobanks based on random samples of population typically showed slightly lower cancer incidence rates than the general population, presumably due to better participation rates among health-conscious subjects. On the other hand, biobanks including samples for viral screening or clinical testing showed 1.5 to 2.1 fold increased incidence of cancer. This excess was very high immediately after sampling, but for some cancer sites remained elevated for years after clinical sampling. So far, more than 100 000 malignant neoplasms have occurred after sample donation, and the annual increase of the cancer cases in these cohorts is about 10 000. The estimates on the population-representativity of the biobanks will assist in interpretation of generalizability of results of future studies based on these samples, and the systematic tabulations of numbers of cancer cases will serve in study power estimations. The present paper summarizes optimal study designs of biobank-based studies of cancer.