Contemporary consensus proposal on criteria and classification of eosinophilic disorders and related syndromes

Eosinophilia is an important indicator of various neoplastic and nonneoplastic conditions. Depending on the underlying disease and mechanisms, eosinophil infiltration can lead to organ dysfunction, clinical symptoms, or both. During the past 2 decades, several different classifications of eosinophilic disorders and related syndromes have been proposed in various fields of medicine. Although criteria and definitions are, in part, overlapping, no global consensus has been presented to date. The Year 2011 Working Conference on Eosinophil Disorders and Syndromes was organized to update and refine the criteria and definitions for eosinophilic disorders and to merge prior classifications in a contemporary multidisciplinary schema. A panel of experts from the fields of immunology, allergy, hematology, and pathology contributed to this project. The expert group agreed on unifying terminologies and criteria and a classification that delineates various forms of hypereosinophilia, including primary and secondary variants based on specific hematologic and immunologic conditions, and various forms of the hypereosinophilic syndrome. For patients in whom no underlying disease or hypereosinophilic syndrome is found, the term hypereosinophilia of undetermined significance is introduced. The proposed novel criteria, definitions, and terminologies should assist in daily practice, as well as in the preparation and conduct of clinical trials.

Identification and in silico analyses of novel TGFBR1 and TGFBR2 mutations in Marfan syndrome-related disorders

Very recently, heterozygous mutations in the genes encoding transforming growth factor beta receptors I (TGFBR1) and II (TGFBR2) have been reported in Loeys-Dietz aortic aneurysm syndrome (LDS). In addition, dominant TGFBR2 mutations have been identified in Marfan syndrome type 2 (MFS2) and familial thoracic aortic aneurysms and dissections (TAAD). In the past, mutations of these genes were associated with atherosclerosis and several human cancers. Here, we report a total of nine novel and one known heterozygous sequence variants in the TGFBR1 and TGFBR2 genes in nine of 70 unrelated individuals with MFS-like phenotypes who previously tested negative for mutations in the gene encoding the extracellular matrix protein fibrillin-1 (FBN1). To assess the pathogenic impact of these sequence variants, in silico analyses were performed by the PolyPhen, SIFT, and Fold-X algorithms and by means of a 3D homology model of the TGFBR2 kinase domain. Our results showed that in all but one of the patients the pathogenic effect of at least one sequence variant is highly probable (c.722C > T, c.799A > C, and c.1460G > A in TGFBR1 and c.773T > G, c.1106G > T, c.1159G > A, c.1181G > A, and c.1561T > C in TGFBR2). These deleterious alleles occurred de novo or segregated with the disease in the families, indicating a causative association between the sequence variants and clinical phenotypes. Since TGFBR2 mutations found in patients with MFS-related disorders cannot be distinguished from heterozygous TGFBR2 mutations reported in tumor samples, we emphasize the importance of segregation analysis in affected families. In order to be able to find the mutation that is indeed responsible for a MFS-related phenotype, we also propose that genetic testing for sequence alterations in TGFBR1 and TGFBR2 should be complemented by mutation screening of the FBN1 gene.

Non-Substance-Related Disorders: Gambling disorder and internet addiction

Behavioral addictions are highly prevalent and have a major individual and societal impact. Moreover, given the availability and increase of potentially addictive activities in our societal development (e.g. internet, gaming, online pornography) an increase in these types of behavioral disorders is very likely. Gambling Disorders are best studied among the non-chemical addictions. However, effective treatment interventions need to be further developed, in particular for Internet Addiction. Most of the available evidence supports behavioral interventions as first line treatment. Specifically for Gambling Disorder, pharmacotherapy can be an useful augmentation.. Psychiatric comorbidities are frequent in patients with behavioral addictions and negatively affect the course of non-substance-related disorders. Concurrent treatment of these comorbid disorders is advised, although there is a clear need of conducting studies evaluating the effectiveness of integrated treatment approaches.

Immunophenotyping of acute leukemia and lymphoproliferative disorders: a consensus proposal of the European LeukemiaNet Work Package 10

The European LeukemiaNet (ELN), workpackage 10 (WP10) was designed to deal with diagnosis matters using morphology and immunophenotyping. This group aimed at establishing a consensus on the required reagents for proper immunophenotyping of acute leukemia and lymphoproliferative disorders. Animated discussions within WP10, together with the application of the Delphi method of proposals circulation, quickly led to post-consensual immunophenotyping panels for disorders on the ELN website. In this report, we established a comprehensive description of these panels, both mandatory and complementary, for both types of clinical conditions. The reason for using each marker, sustained by relevant literature information, is provided in detail. With the constant development of immunophenotyping techniques in flow cytometry and related software, this work aims at providing useful guidelines to perform the most pertinent exploration at diagnosis and for follow-up, with the best cost benefit in diseases, the treatment of which has a strong impact on health systems.

miR-34a and miR-15a/16 are co-regulated in non-small cell lung cancer and control cell cycle progression in a synergistic and Rb-dependent manner

microRNAs (miRNAs) are small non-coding RNAs that are frequently involved in carcinogenesis. Although many miRNAs form part of integrated networks, little information is available how they interact with each other to control cellular processes. miR-34a and miR-15a/16 are functionally related; they share common targets and control similar processes including G1-S cell cycle progression and apoptosis. The aim of this study was to investigate the combined action of miR-34a and miR-15a/16 in non-small cell lung cancer (NSCLC) cells.

Outcome predictors of radical prostatectomy followed by adjuvant androgen deprivation in patients with clinical high risk prostate cancer and pT3 surgical margin positive disease

Patients with high risk prostate cancer with pT3 tumor and positive surgical margins have a high risk of biochemical failure after radical prostatectomy and adjuvant androgen deprivation therapy. Predictors of cancer related death in this patient group are necessary.

A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders

BACKGROUND: The recurrent ~600 kb 16p11.2 BP4-BP5 deletion is among the most frequent known genetic aetiologies of autism spectrum disorder (ASD) and related neurodevelopmental disorders. OBJECTIVE: To define the medical, neuropsychological, and behavioural phenotypes in carriers of this deletion. METHODS: We collected clinical data on 285 deletion carriers and performed detailed evaluations on 72 carriers and 68 intrafamilial non-carrier controls. RESULTS: When compared to intrafamilial controls, full scale intelligence quotient (FSIQ) is two standard deviations lower in carriers, and there is no difference between carriers referred for neurodevelopmental disorders and carriers identified through cascade family testing. Verbal IQ (mean 74) is lower than non-verbal IQ (mean 83) and a majority of carriers require speech therapy. Over 80% of individuals exhibit psychiatric disorders including ASD, which is present in 15% of the paediatric carriers. Increase in head circumference (HC) during infancy is similar to the HC and brain growth patterns observed in idiopathic ASD. Obesity, a major comorbidity present in 50% of the carriers by the age of 7 years, does not correlate with FSIQ or any behavioural trait. Seizures are present in 24% of carriers and occur independently of other symptoms. Malformations are infrequently found, confirming only a few of the previously reported associations. CONCLUSIONS: The 16p11.2 deletion impacts in a quantitative and independent manner FSIQ, behaviour and body mass index, possibly through direct influences on neural circuitry. Although non-specific, these features are clinically significant and reproducible. Lastly, this study demonstrates the necessity of studying large patient cohorts ascertained through multiple methods to characterise the clinical consequences of rare variants involved in common diseases.

Estrogen receptor β expression and androgen receptor phosphorylation correlate with a poor clinical outcome in hormone-naive prostate cancer and are elevated in castration-resistant disease

Patients with advanced prostate cancer (PC) are usually treated with androgen withdrawal. While this therapy is initially effective, nearly all PCs become refractory to it. As hormone receptors play a crucial role in this process, we constructed a tissue microarray consisting of PC samples from 107 hormone-naïve (HN) and 101 castration-resistant (CR) PC patients and analyzed the androgen receptor (AR) gene copy number and the protein expression profiles of AR, Serin210-phosphorylated AR (pAR(210)), estrogen receptor (ER)β, ERα and the proliferation marker Ki67. The amplification of the AR gene was virtually restricted to CR PC and was significantly associated with increased AR protein expression (P<0.0001) and higher tumor cell proliferation (P=0.001). Strong AR expression was observed in a subgroup of HN PC patients with an adverse prognosis. In contrast, the absence of AR expression in CR PC was significantly associated with a poor overall survival. While pAR(210) was predominantly found in CR PC patients (P<0.0001), pAR(210) positivity was observed in a subgroup of HN PC patients with a poor survival (P<0.05). Epithelial ERα expression was restricted to CR PC cells (9%). ERβ protein expression was found in 38% of both HN and CR PCs, but was elevated in matched CR PC specimens. Similar to pAR(210), the presence of ERβ in HN patients was significantly associated with an adverse prognosis (P<0.005). Our results strongly suggest a major role for pAR(210) and ERβ in HN PC. The expression of these markers might be directly involved in CR tumor growth.

Childhood cancer and residential exposure to highways: a nationwide cohort study.

Children living near highways are exposed to higher concentrations of traffic-related carcinogenic pollutants. Several studies reported an increased risk of childhood cancer associated with traffic exposure, but the published evidence is inconclusive. We investigated whether cancer risk is associated with proximity of residence to highways in a nation-wide cohort study including all children aged <16 years from Swiss national censuses in 1990 and 2000. Cancer incidence was investigated in time to event analyses (1990-2008) using Cox proportional hazards models and incidence density analyses (1985-2008) using Poisson regression. Adjustments were made for socio-economic factors, ionising background radiation and electromagnetic fields. In time to event analysis based on 532 cases the adjusted hazard ratio for leukaemia comparing children living <100 m from a highway with unexposed children (≥500 m) was 1.43 (95 % CI 0.79, 2.61). Results were similar in incidence density analysis including 1367 leukaemia cases (incidence rate ratio (IRR) 1.57; 95 % CI 1.09, 2.25). Associations were similar for acute lymphoblastic leukaemia (IRR 1.64; 95 % CI 1.10, 2.43) and stronger for leukaemia in children aged <5 years (IRR 1.92; 95 % CI 1.22, 3.04). Little evidence of association was found for other tumours. Our study suggests that young children living close to highways are at increased risk of developing leukaemia.

The Role of Autophagy in Cancer and Chemotherapy

Resistance to current chemo- and radiation therapy is the principal problem in anticancer treatment. Although intensively investigated, the therapeutic outcome is still far from satisfactory. Among the multiple factors which contribute to the drug resistance in cancer cells, the involvement of autophagy is becoming more and more evident. Autophagy describes a cellular self-digestion process, in which cytoplasmic elements can be selectively engulfed and finally degraded in autophagolysosomes to supply nutrients and building blocks for the cells. Autophagy controls cellular homeostasis and can be induced in response to stresses, like hypoxia and growth factor withdrawal. Since the essential physiological function of autophagy is to maintain cellular metabolic balance, dysregulated autophagy has been found associated with multiple diseases, including cancer. Interestingly, the role of autophagy in cancer is two-sided; it can be pro- or antitumor. Autophagy can suppress tumor formation, for example, by controlling cell proliferation and the production of reactive oxygen species. On the other hand, autophagy can provide nutrients to the tumor cells to support tumor growth under nutrition-limiting conditions, thereby promoting tumor development. This ambivalent behavior is also evident in anticancer therapy: By inducing autophagic cell death, autophagy has been shown to potentiate the cytotoxicity of chemotherapeutic drugs, but autophagy has also been linked to drug resistance, since inhibiting autophagy has been found to sensitize tumor cells toward anticancer drug-induced cell death. In this chapter, we will focus on the dual role of autophagy in tumorigenesis and chemotherapy, will classify autophagy inducers and inhibitors used in anticancer treatment, and will discuss topics related to future drug development which have arisen.

Androgen receptors are differentially expressed in Gleason patterns of prostate cancer and down-regulated in matched lymph node metastases

Androgen receptor (AR) expression profile in the different Gleason patterns (GP) of primary prostate cancers and nodal metastases is unknown. More information about AR distribution is needed to optimize evaluation methods and to better understand the role of AR in development and progression of prostate cancer.

Meta-analyses qualify metzincins and related genes as acute rejection markers in renal transplant patients

Definition of acute renal allograft rejection (AR) markers remains clinically relevant. Features of T-cell-mediated AR are tubulointerstitial and vascular inflammation associated with excessive extracellular matrix (ECM) remodeling, regulated by metzincins, including matrix metalloproteases (MMP). Our study focused on expression of metzincins (METS), and metzincins and related genes (MARGS) in renal allograft biopsies using four independent microarray data sets. Our own cases included normal histology (N, n = 20), borderline changes (BL, n = 4), AR (n = 10) and AR + IF/TA (n = 7). MARGS enriched in all data sets were further examined on mRNA and/or protein level in additional patients. METS and MARGS differentiated AR from BL, AR + IF/TA and N in a principal component analysis. Their expression changes correlated to Banff t- and i-scores. Two AR classifiers, based on METS (including MMP7, TIMP1), or on MARGS were established in our own and validated in the three additional data sets. Thirteen MARGS were significantly enriched in AR patients of all data sets comprising MMP7, -9, TIMP1, -2, thrombospondin2 (THBS2) and fibrillin1. RT-PCR using microdissected glomeruli/tubuli confirmed MMP7, -9 and THBS2 microarray results; immunohistochemistry showed augmentation of MMP2, -9 and TIMP1 in AR. TIMP1 and THBS2 were enriched in AR patient serum. Therefore, differentially expressed METS and MARGS especially TIMP1, MMP7/-9 represent potential molecular AR markers.

Regulation of placental growth by aldosterone and cortisol

During pregnancy, trophoblasts grow to adapt the feto-maternal unit to fetal requirements. Aldosterone and cortisol levels increase, the latter being inactivated by a healthy placenta. By contrast, preeclamptic placental growth is reduced while aldosterone levels are low and placental cortisol tissue levels are high due to improper deactivation. Aldosterone acts as a growth factor in many tissues, whereas cortisol inhibits growth. We hypothesized that in preeclampsia low aldosterone and enhanced cortisol availability might mutually affect placental growth and function. Proliferation of cultured human trophoblasts was time- and dose-dependently increased with aldosterone (P < 0.04 to P < 0.0001) and inhibited by spironolactone and glucocorticoids (P < 0.01). Mineralo- and glucocorticoid receptor expression and activation upon agonist stimulation was verified by visualization of nuclear translocation of the receptors. Functional aldosterone deficiency simulated in pregnant mice by spironolactone treatment (15 μg/g body weight/day) led to a reduced fetal umbilical blood flow (P < 0.05). In rat (P < 0.05; R(2) = 0.2055) and human (X(2) = 3.85; P = 0.0249) pregnancy, placental size was positively related to plasma aldosterone. Autocrine production of these steroid hormones was excluded functionally and via the absence of specific enzymatic transcripts for CYP11B2 and CYP11B1. In conclusion, activation of mineralocorticoid receptors by maternal aldosterone appears to be required for trophoblast growth and a normal feto-placental function. Thus, low aldosterone levels and enhanced cortisol availability may be one explanation for the reduced placental size in preeclampsia and related disorders.

Patients with substance use and personality disorders: a comparison of patient characteristics, treatment process, and outcomes in Swiss and U.S. substance use disorder programs

Cross-cultural comparisons may increase our understanding of different models of substance use treatment and help identify consistent associations between patients' characteristics, treatment conditions, and outcomes.