Endocrine immune-related adverse events: Adrenal, parathyroid, diabetes insipidus, and lipoatrophy.

Immune checkpoint inhibitors are being prescribed increasingly widely for a range of malignancies. They are effective at treating certain cancers, but also have significant side effects. Evidence suggests that efficacy is greatest in patients who experience one or more immune-related adverse events (irAEs). Common irAEs include skin and hepatic reactions, and a range of immune-related endocrinopathies. These include hypophysitis, thyroid disease, and autoimmune diabetes mellitus, and rarer endocrinopathies such as primary adrenal insufficiency, diabetes insipidus, parathyroid disease, autoimmune polyglandular syndrome, lipodystrophy, and ACTH-dependent Cushing's syndrome. Herein, we review the current literature related to these rarer immunotherapy-induced endocrinopathies.

Impact of Inter-Individual Variance in the Expression of a Radiation-Responsive Gene Panel Used for Triage.

In previous studies we determined a gene expression signature in baboons for predicting the severity of hematological acute radiation syndrome. We subsequently validated a set of eight of these genes in leukemia patients undergoing total-body irradiation. In the current study, we addressed the effect of intra-individual variability on the basal level of expression of those eight radiation-responsive genes identified previously, by examining baseline levels in 200 unexposed healthy human donors (122 males and 88 females with an average age of 46 years) using real-time PCR. In addition to the eight candidate genes ( DAGLA, WNT3, CD177, PLA2G16, WLS, POU2AF1, STAT4 and PRF1), we examined two more genes ( FDXR and DDB2) widely used in ex vivo whole blood experiments. Although significant sex- (seven genes) and age-dependent (two genes) differences in expression were found, the fold changes ranged only between 1.1-1.6. These were well within the twofold differences in gene expression generally considered to represent control values. Age and sex contributed less than 20-30% to the complete inter-individual variance, which is calculated as the fold change between the lowest (reference) and the highest Ct value minimum-maximum fold change (min-max FC). Min-max FCs ranging between 10-17 were observed for most genes; however, for three genes, min-max FCs of complete inter-individual variance were found to be 37.1 ( WNT3), 51.4 ( WLS) and 1,627.8 ( CD177). In addition, to determine whether discrimination between healthy and diseased baboons might be altered by replacing the published gene expression data of the 18 healthy baboons with that of the 200 healthy humans, we employed logistic regression analysis and calculated the area under the receiver operating characteristic (ROC) curve. The additional inter-individual variance of the human data set had either no impact or marginal impact on the ROC area, since up to 32-fold change gene expression differences between healthy and diseased baboons were observed.

The Rb1 tumour suppressor gene modifies telomeric chromatin architecture by regulating TERRA expression.

The tumour suppressor gene (Rb1) is necessary for the maintenance of telomere integrity in osteoblastic cells. We now show that the compaction of telomeric chromatin and the appropriate histone modifications of telomeric DNA are both dependent upon Rb1-mediated transcription of the telomere-derived long non-coding RNA TERRA. Expression of TERRA was reduced in Rb1 haploinsufficient cells, and further decreased by shRNA-mediated reduction of residual Rb1 expression. Restoration of Rb1 levels through lentiviral transduction was sufficient to reestablish both transcription of TERRA and condensation of telomeric chromatin. The human chromosome 15q TERRA promoter contains predicted retinoblastoma control elements, and was able to confer Rb1-dependent transcription upon a promoterless reporter gene. Chromatin immunoprecipitation revealed preferential binding of phosphorylated over non-phosphorylated Rb1 at the TERRA promoter. As Rb1-deficient cells show increased genomic instability we suggest that this novel non-canonical action of Rb1 may contribute to the tumour suppressive actions of Rb1.

The effects of policy actions to improve population dietary patterns and prevent diet-related non-communicable diseases: scoping review.

Poor diet generates a bigger non-communicable disease (NCD) burden than tobacco, alcohol and physical inactivity combined. We reviewed the potential effectiveness of policy actions to improve healthy food consumption and thus prevent NCDs. This scoping review focused on systematic and non-systematic reviews and categorised data using a seven-part framework: price, promotion, provision, composition, labelling, supply chain, trade/investment and multi-component interventions. We screened 1805 candidate publications and included 58 systematic and non-systematic reviews. Multi-component and price interventions appeared consistently powerful in improving healthy eating. Reformulation to reduce industrial trans fat intake also seemed very effective. Evidence on food supply chain, trade and investment studies was limited and merits further research. Food labelling and restrictions on provision or marketing of unhealthy foods were generally less effective with uncertain sustainability. Increasingly strong evidence is highlighting potentially powerful policies to improve diet and thus prevent NCDs, notably multi-component interventions, taxes, subsidies, elimination and perhaps trade agreements. The implications for policy makers are becoming clearer.

Mobilization without immune depletion fails to restore immunological tolerance or preserve beta cell function in recent onset type 1 diabetes.

Granulocyte colony-stimulating factor (G-CSF) has been used to restore immune competence following chemoablative cancer therapy and to promote immunological tolerance in certain settings of autoimmunity. Therefore, we tested the potential of G-CSF to impact type 1 diabetes (T1D) progression in patients with recent-onset disease [n = 14; n = 7 (placebo)] and assessed safety, efficacy and mechanistic effects on the immune system. We hypothesized that pegylated G-CSF (6 mg administered subcutaneously every 2 weeks for 12 weeks) would promote regulatory T cell (Treg) mobilization to a degree capable of restoring immunological tolerance, thus preventing further decline in C-peptide production. Although treatment was well tolerated, G-CSF monotherapy did not affect C-peptide production, glycated haemoglobin (HbA1c) or insulin dose. Mechanistically, G-CSF treatment increased circulating neutrophils during the 12-week course of therapy (P < 0·01) but did not alter Treg frequencies. No effects were observed for CD4(+) : CD8(+) T cell ratio or the ratio of naive : memory (CD45RA(+)/CD45RO(+)) CD4(+) T cells. As expected, manageable bone pain was common in subjects receiving G-CSF, but notably, no severe adverse events such as splenomegaly occurred. This study supports the continued exploration of G-CSF and other mobilizing agents in subjects with T1D, but only when combined with immunodepleting agents where synergistic mechanisms of action have previously demonstrated efficacy towards the preservation of C-peptide.

Realising the European network of biodosimetry: RENEB-status quo.

Creating a sustainable network in biological and retrospective dosimetry that involves a large number of experienced laboratories throughout the European Union (EU) will significantly improve the accident and emergency response capabilities in case of a large-scale radiological emergency. A well-organised cooperative action involving EU laboratories will offer the best chance for fast and trustworthy dose assessments that are urgently needed in an emergency situation. To this end, the EC supports the establishment of a European network in biological dosimetry (RENEB). The RENEB project started in January 2012 involving cooperation of 23 organisations from 16 European countries. The purpose of RENEB is to increase the biodosimetry capacities in case of large-scale radiological emergency scenarios. The progress of the project since its inception is presented, comprising the consolidation process of the network with its operational platform, intercomparison exercises, training activities, proceedings in quality assurance and horizon scanning for new methods and partners. Additionally, the benefit of the network for the radiation research community as a whole is addressed.

MiR-221/-222 differentiate prognostic groups in advanced breast cancers and influence cell invasion.

BACKGROUND: MiR-221/-222 are frequently overexpressed in breast cancer and are associated with increased malignancy. The specific modification of microRNAs (miRNAs) expression could be a promising strategy in breast cancer therapy, leading to the suppression of tumourigenic processes in tumour cells. METHODS: MiR-221/-222 expressions were analysed in 86 breast cancer tissues by quantitative RT-PCR and tested for correlation with immunohistochemistry data and clinical follow-up. In vitro assays were conducted using human breast cancer cell lines with lentiviral overexpression of miR-221/-222. RESULTS: In tumour tissues, miR-221/-222 were associated with the occurrence of distant metastases. In particular, high levels of miR-221 were revealed to have a high prognostic impact for the identification of significantly different groups with advanced tumours. MiR-221/-222 overexpression strongly increased cell proliferation and invasion in vitro. Following miR-221/-222 overexpression an increased uPAR expression and cell invasion were observed. CONCLUSION: This study demonstrates a significant role for highly expressed miR-221/-222 in advanced breast cancers allowing for the identification of significantly different prognostic groups, particularly for HER2-positive and lymph-node-positive breast cancers. Considering that miR-221/-222 are strongly involved in cell invasion, these miRNAs may be promising markers for breast cancer prognosis and therapy.

A mechanistic model for medulloblastoma induction in mice.

Medulloblastomas in Patched heterozygous mice (Ptc1(+/-) mice) are induced with high probability by ionizing radiation applied in the immediate post-natal period. A mathematical model is described here that accommodates the dependence of the medulloblastoma incidence on dose, age at exposure and age. The model assumes that the first step in the development of the cancer is already present in all cells of the patched mouse due to germ-line inactivation of one allele of the patched tumor suppressor gene. The subsequent rate-limiting step is dependent linearly on dose at least up to 3 Gy. The observed strong decrease in carcinogenic effect of radiation between exposure on day 1 and day 10 is described by a physiological elimination of target cells during post-natal maturation of the brain. A single malignant cell develops into a tumor following a gamma-distribution with mean of about 160 days. The multiplicity of medulloblastomas is predicted.

Influence of Tyrphostin AG490 on the expression of diabetes-associated markers in human adipocytes.

Tyrosine kinase inhibitors (TKi) hold promise as a treatment for a variety of disorders ranging from those in oncology to diseases thought as immune mediated. Tyrphostin AG490 is a potent Jak-Stat TKi shown effective in the prevention of allograft transplant rejection, experimental autoimmune disease, as well as the treatment of cancer. However, given its ability to modulate this important but pleiotropic intracellular pathway, we thought that it is important to examine its effects on glucose metabolism and expression of major transcription factors and adipokines associated with insulin insensitivity and diabetes. We investigated the metabolic effects of AG490 on glucose levels in vivo using an animal model of diabetes, nonobese diabetic (NOD) mice, and transcription factor expression through assessment of human adipocytes. AG490 treatment of young nondiabetic NOD mice significantly reduced blood glucose levels (p = 0.002). In vitro, treatment of adipocytes with rosiglitazone, an insulin sensitizer that binds to peroxisome proliferator-activated receptor (PPAR) receptors and increases the adipocyte response to insulin, significantly increased the expression of the antidiabetic adipokine adiponectin. Importantly, the combination of rosiglitazone plus Tyrphostin AG490 further increased this effect and was specifically associated with significant upregulation of C-enhanced binding protein (C/EBP) (p < 0.0001). In terms of the mechanism underlying this action, regulatory regions of the PPARγ, ADIPOQ, and C/EBP contain the Stat5 DNA-binding sequences and were demonstrated, by gel shift experiments in vitro. These data suggest that blocking Jak-Stat signaling with AG490 reduces blood glucose levels and modulates the expression of transcription factors previously associated with diabetes, thereby supporting its potential as a therapy for this disease.

Realising the European Network of Biodosimetry (RENEB).

In Europe, a network for biological dosimetry has been created to strengthen the emergency preparedness and response capabilities in case of a large-scale nuclear accident or radiological emergency. Through the RENEB (Realising the European Network of Biodosimetry) project, 23 experienced laboratories from 16 European countries will establish a sustainable network for rapid, comprehensive and standardised biodosimetry provision that would be urgently required in an emergency situation on European ground. The foundation of the network is formed by five main pillars: (1) the ad hoc operational basis, (2) a basis of future developments, (3) an effective quality-management system, (4) arrangements to guarantee long-term sustainability and (5) awareness of the existence of RENEB. RENEB will thus provide a mechanism for quick, efficient and reliable support within the European radiation emergency management. The scientific basis of RENEB will concurrently contribute to increased safety in the field of radiation protection.

Lymph node characterization in vivo using endoscopic ultrasound spectrum analysis with electronic array echo endoscopes.

Our purpose was to demonstrate the use of radiofrequency spectral analysis to distinguish between benign and malignant lymph nodes with data obtained using electronic array echo endoscopes, as we have done previously using mechanical echo endoscopes. In a prospective study, images were obtained from eight patients with benign-appearing lymph nodes and 11 with malignant lymph nodes, as verified by fine-needle aspiration. Midband fit, slope, intercept, correlation coefficient, and root-mean-square (RMS) deviation from a linear regression of the calibrated power spectra were determined and compared between the groups. Significant differences were observable for mean midband fit, intercept, and RMS deviation (t test P < 0.05). For benign (n = 16) vs. malignant (n = 12) lymph nodes, midband fit and RMS deviation provided classification with 89 % accuracy and area under receiver operating characteristic (ROC) curve of 0.95 based on linear discriminant analysis. We concluded that the mean spectral parameters of the backscattered signals from electronic array echo endoscopy can provide a noninvasive method to quantitatively discriminate between benign and malignant lymph nodes.

Clinically relevant fatigue in recurrence-free prostate cancer survivors.

BACKGROUND: Little is known about the prevalence and associations of clinically relevant fatigue (CRF) in recurrence-free prostate cancer survivors. PATIENTS AND METHODS: Four hundred and sixteen recurrence-free prostate cancer survivors who were >1 year post-radiotherapy or radical prostatectomy were surveyed. The prevalence of CRF (defined as Brief Fatigue Inventory >3) was determined and compared with a noncancer control group. Other measures included the Hospital Anxiety and Depression Scale, International Prostate Symptom Score, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire. Relationships between these factors and CRF were explored in univariate and multivariate analyses. RESULTS: Analyzable data were obtained from 91% (377/416) of patients. The prevalence of CRF was 29% (108/377) versus 16% (10/63) in the controls (P=0.031). CRF was more common in post-radiotherapy than in post-prostatectomy 33% (79/240) versus 22% (29/133), P=0.024. However, when other factors (current depression, anxiety, urinary symptoms, medical comorbidities, pain and insomnia) were controlled for, previous treatment did not predict CRF. Current depression [Hospital Anxiety and Depression Scale≥8 was by far the strongest association [odds ratio 9.9, 95% confidence interval 4.2-23.5)]. CONCLUSIONS: Almost one-third of recurrence-free prostate cancer survivors report CRF. Depression, anxiety, urinary symptoms, pain and insomnia measured at outcome are more strongly associated than type of cancer treatment previously received.

Clinically relevant fatigue in men with hormone-sensitive prostate cancer on long-term androgen deprivation therapy.

BACKGROUND: The purpose of the study was to determine the prevalence and associations of clinically relevant fatigue (CRF) in men with biochemically controlled prostate cancer on long-term androgen deprivation therapy (ADT). PATIENTS AND METHODS: One hundred and ninety-eight men were surveyed and the prevalence of CRF (Brief Fatigue Inventory score >3) determined. Associations with other measures (Hospital Anxiety and Depression Scale; International Prostate Symptom Score; European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire; Brief Pain Inventory worst pain; clinical and demographic information) were explored in univariate and multivariate analyses. RESULTS: Eight-one per cent (160 of 198) of questionnaires were analysable. CRF prevalence was 43% (68 of 160). CRF associations included moderate/severe urinary symptoms, anxiety and medical co-morbidities; the strongest associations were depression [odds ratio (OR) 9.8, 95% confidence interval (CI) 4.3-22.8] and pain (OR 9.2, 95% CI 4.0-21.5). After controlling for other factors, the independent associations were depression (OR 4.7, 95% CI 1.6-14.0) and pain (OR 3.1, 95% CI 1.0-8.9). There was no association with age, disease burden or treatment duration. CONCLUSIONS: Two-fifths of men with biochemically controlled prostate cancer on long-term ADT report CRF that interferes with function. Management aimed at improving CRF should address depression and pain.

Combinatorial treatment of bone marrow stem cells and stromal cell-derived factor 1 improves glycemia and insulin production in diabetic mice.

Transdifferentiation of stem cells into insulin-producing cells for the treatment of diabetes have shown promising but inconsistent results. We examined the potential for attracting bone marrow stem cells (BMSCs) to the pancreas using a chemokine, stromal cell-derived factor 1 (SDF-1). SDF-1 treatment markedly increased the number of GFP labeled BMSCs in the pancreas, but surprisingly, the majority was observed in liver. The liver cells had typical pancreatic endocrine cell gene expression including insulin I, insulin II, PDX-1, somatostatin, and glucagon. Combined treatment with SDF-1 and BMSC transplant reduced hyperglycemia and prolonged the long-term survival of diabetic mice, and a sub group had complete normoglycemia (<150 mg/dl), restored blood insulin levels, and normal glucose tolerance. Our results suggest that SDF-1 could potentially be used to improve the homing of stem cells and ß-cell regeneration. The mechanism appears to involve an increase in insulin producing cells mainly in the liver.

Opposite modifying effects of HR and NHEJ deficiency on cancer risk in Ptc1 heterozygous mouse cerebellum.

Heterozygous Patched1 (Ptc1(+/-)) mice are prone to medulloblastoma (MB), and exposure of newborn mice to ionizing radiation dramatically increases the frequency and shortens the latency of MB. In Ptc1(+/-) mice, MB is characterized by loss of the normal remaining Ptc1 allele, suggesting that genome rearrangements may be key events in MB development. Recent evidence indicates that brain tumors may be linked to defects in DNA-damage repair processes, as various combinations of targeted deletions in genes controlling cell-cycle checkpoints, apoptosis and DNA repair result in MB in mice. Non-homologous end joining (NHEJ) and homologous recombination (HR) contribute to genome stability, and deficiencies in either pathway predispose to genome rearrangements. To test the role of defective HR or NHEJ in tumorigenesis, control and irradiated Ptc1(+/-) mice with two, one or no functional Rad54 or DNA-protein kinase catalytic subunit (DNA-PKcs) alleles were monitored for MB development. We also examined the effect of Rad54 or DNA-PKcs deletion on the processing of endogenous and radiation-induced double-strand breaks (DSBs) in neural precursors of the developing cerebellum, the cells of origin of MB. We found that, although HR and NHEJ collaborate in protecting cells from DNA damage and apoptosis, they have opposite roles in MB tumorigenesis. In fact, although Rad54 deficiency increased both spontaneous and radiation-induced MB development, DNA-PKcs disruption suppressed MB tumorigenesis. Together, our data provide the first evidence that Rad54-mediated HR in vivo is important for suppressing tumorigenesis by maintaining genomic stability.

Cadmium, copper, iron, and zinc concentrations in kidneys of grey wolves, Canis lupus, from Alaska, Idaho, Montana (USA) and the Northwest Territories (Canada).

Cadmium, copper, iron, and zinc levels were measured in the kidneys of 115 grey wolves (Canis lupus) from Idaho, Montana and Alaska (United States), and from the Northwest Territories (Canada). No significant differences in the levels of iron or copper were observed between locations, but wolf kidneys from more northern locations had significantly higher cadmium levels (Alaska > Northwest Territories > Montana ≈ Idaho), and wolves from Alaska showed significantly higher zinc than other locations. Additionally, female wolves in Alaska had higher iron levels than males, and adult wolves in Montana had higher copper levels than subadults.

Influence of serum and soluble CD25 (sCD25) on regulatory and effector T-cell function in hepatocellular carcinoma.

Our previous studies showed that high levels of soluble CD25 (sCD25) in the serum of patients with hepatocellular carcinoma (HCC) correlated with blunted effector T-cells (Teff) responses, tumour burden and poor survival. Understanding the interactions between Teff, CD4+CD25+ regulatory T cells (Treg) and soluble factors can identify novel therapeutic targets. In this study, we characterize the mechanisms by which HCC serum and sCD25 mediate suppression of Teff and evaluate the effect of sCD25 on the suppression assays with normal healthy control cells (NHC) at a 1:1 Treg to Teff cell ratio to determine whether sCD25 has any impact on Treg suppression. HCC serum and sCD25 suppressed Teff proliferation and downregulated CD25 expression on HCC Teff in a dose-dependent fashion with sCD25 doses above 3000 pg/ml. Treg from HCC and cirrhosis patients suppressed proliferation of target CD4+CD25- Teff in serum-free medium (SFM). HCC Treg showed a higher degree of suppression than cirrhosis-derived Treg. In contrast, Treg from NHC did not suppress target Teff in SFM. However, isolated Treg from all three study subjects (HCC, cirrhosis and NHC) suppressed CD4+CD25- Teff in serum conditions or in the presence of sCD25 in the range 6000-12,000 pg/ml. In conclusion, downregulation of CD25 cell surface expression on Teff is part of the overall suppressive mechanism of sCD25 and HCC serum on Teff responses. The observed sCD25 and HCC serum-mediated suppression is further influenced via novel immune-inhibitory interaction between CD4+CD25+ Treg and sCD25.

Incidence of leukaemia and other malignant diseases following injections of the short-lived alpha-emitter 224Ra into man.

We performed an epidemiological study on 1,471 ankylosing spondylitis patients treated with repeated intravenous injections of the short lived alpha-emitter (224)Ra (excluding radiation therapy with X-rays) between 1948 and 1975. These patients have been followed together with a control group of 1,324 ankylosing spondylitis patients treated neither with radioactive drugs nor with X-rays. The mean follow-up time was 26.3 years in the exposed and 24.6 years in the control group. To date, causes of death have been ascertained for 1,006 exposed patients and 1,072 controls. Special emphasis was placed on the reporting of malignant diseases. Expected numbers of cases were computed for the age, sex and calendar year distribution of both groups using cancer registry incidence rates. In the exposed group 18 cases of kidney cancer (vs. 9.1 cases expected, P < 0.01) and 4 malignant thyroid tumours (vs. 1.2 cases expected, P = 0.03) were observed. In the control group the observed cases for these tumours were not significantly elevated. The most striking observation, however, were the 21 cases of leukaemia in the exposed group (vs. 6.8 cases expected, P < 0.001) compared to 12 cases of leukaemia in the control group (vs. 7.5 cases expected). Further sub-classification of the leukaemias demonstrated a high increase of myeloid leukaemia in the exposed group (12 cases observed vs. 2.9 cases expected, P < 0.001), and out of these, especially a high excess of acute myeloid leukaemias (7 cases observed vs. 1.8 expected, P = 0.003). In the controls the observed cases are within the expected range (4 myeloid leukaemias vs. 3.1 cases). This increase in total leukaemias as well as particularly in myeloid leukaemias is significant in direct comparison between the exposed and control groups too (P < 0.05). The enhanced leukaemia incidence in the exposed group is in line with the observation of increased leukaemia incidence in mice injected with (224)Ra.

Pancreatic adenocarcinoma patients with localised chronic severe pancreatitis show an increased number of single beta cells, without alterations in fractional insulin area.

AIMS/HYPOTHESIS: Recent histological analysis of pancreases obtained from patients with long-standing type 1 diabetes identified chronic islet inflammation and limited evidence suggestive of beta cell replication. Studies in rodent models also suggest that beta cell replication can be induced by certain inflammatory cytokines and by gastrin. We therefore tested the hypothesis that beta cell replication is observed in non-autoimmune human pancreatic disorders in which localised inflammation or elevated gastrin levels are present. METHODS: Resected operative pancreatic specimens were obtained from patients diagnosed with primary adenocarcinoma (with or without chronic severe pancreatitis) or gastrinoma. Additional pancreatic tissue was obtained from autopsy control patients. Immunohistochemistry was used to assess fractional insulin area, beta cell number and replication rate and differentiation factors relevant to beta cell development. RESULTS: Fractional insulin area was similar among groups. Patients with pancreatic adenocarcinoma and localised chronic severe pancreatitis displayed significant increases in the number of single beta cells, as well as increased beta cell replication rate and levels of neurogenic differentiation 1 in islets. Patients with gastrinoma demonstrated significant increases in the number of single beta cells, but the beta cell replication rate and islet differentiation factor levels were similar to those in the control group. CONCLUSIONS/INTERPRETATION: These findings indicate that chronic severe pancreatic inflammation can be associated with significant effects on beta cell number or replication rate, depending on the distribution of the cells. This information may prove useful for attempts seeking to design therapies aimed at inducing beta cell replication as a means of reversing diabetes.