Taxing across borders: tracking personal wealth and corporate profits

This article attempts to estimate the magnitude of corporate tax avoidance and personal tax evasion through offshore tax havens. US corporations book 20 percent of their profits in tax havens, a tenfold increase since the 1980; their effective tax rate has declined from 30 to 20 percent over the last 15 years, and about two-thirds of this decline can be attributed to increased international tax avoidance. Globally, 8 percent of the world's personal financial wealth is held offshore, costing more than $200 billion to governments every year. Despite ambitious policy initiatives, profit shifting to tax havens and offshore wealth are rising. I discuss the recent proposals made to address these issues, and I argue that the main objective should be to create a world financial registry

Translating '–omics' results into precision medicine for hepatocellular carcinoma

A large-scale comprehensive analysis of hepatocellular carcinoma (HCC) based on the integration of six distinct data platforms has pinpointed novel oncogenic processes and prognostic subgroups. These findings confirm previously identified molecular subclasses and fuel the need for a clear strategy of precision medicine in HCC

Questioning the “Ease” in disease: Was living with HIV a burden or boost during the first wave of Covid-19 in France? A qualitative study (COVIDHIV)

Introduction Clinical research has focused on risk factors and treatment for severe acute respiratory syndrome coronavirus 2 (SARS-COV-2), particularly in people with a comorbidity including the human immunodeficiency virus (HIV), but little attention has been paid to the care pathway. This article aims to show how living with HIV may have been a biopsychosocial burden or boost in care pathways for Covid-19. Method People living with HIV (PLHIV) from 9 clinical centers were invited to participate in this qualitative study. The sampling was purposive with a maximum variation in their sociodemographic profiles. Semi-structured interviews were conducted until data saturation, then coded for thematic analysis, using an inductive general approach. Results We interviewed 34 PLHIV of which 20 had SARS-COV-2 once. They were 24 males, 26 born in France; median age: 55. Twenty had a CD4 number above 500, and all were on antiretroviral therapy (ART). HIV appeared as a burden when Covid-19 symptoms reminded HIV seroconversion, fear of contamination, and triggered questions about ART effectiveness. HIV was not considered relevant when diagnosing Covid-19, caused fear of disclosure when participants sought SARS-COV-2 testing, and its care in hospitals was disrupted by the pandemic. ART-pill fatigue caused avoidance for Covid-19 treatment. As a boost, living with HIV led participants to observe symptoms, to get advice from healthcare professionals, and screening access through them. Some participants could accept the result of screening or a clinical diagnosis out of resilience. Some could consider ART or another drug prescribed by their HIV specialist help them to recover from Covid-19. Conclusion Living with HIV could function as a burden and/or a boost in the care pathways for Covid-19, according to patients’ relationship to their HIV history, comorbidities and representation of ART. Covid-19 in PLHIV needs further qualitative study to gain a more comprehensive assessment of the pandemic’s consequences on their lives and coping strategies

Cellular expression, trafficking, and function of two isoforms of human ULBP5/RAET1G

Background: The activating immunoreceptor NKG2D is expressed on Natural Killer (NK) cells and subsets of T cells. NKG2D contributes to anti-tumour and anti-viral immune responses in vitro and in vivo. The ligands for NKG2D in humans are diverse proteins of the MIC and ULBP/RAET families that are upregulated on the surface of virally infected cells and tumours. Two splicing variants of ULBP5/RAET1G have been cloned previously, but not extensively characterised. Methodology/Principal Findings: We pursue a number of approaches to characterise the expression, trafficking, and function of the two isoforms of ULBP5/RAET1G. We show that both transcripts are frequently expressed in cell lines derived from epithelial cancers, and in primary breast cancers. The full-length transcript, RAET1G1, is predicted to encode a molecule with transmembrane and cytoplasmic domains that are unique amongst NKG2D ligands. Using specific anti-RAET1G1 antiserum to stain tissue microarrays we show that RAET1G1 expression is highly restricted in normal tissues. RAET1G1 was expressed at a low level in normal gastrointestinal epithelial cells in a similar pattern to MICA. Both RAET1G1 and MICA showed increased expression in the gut of patients with celiac disease. In contrast to healthy tissues the RAET1G1 antiserum stained a wide variety or different primary tumour sections. Both endogenously expressed and transfected RAET1G1 was mainly found inside the cell, with a minority of the protein reaching the cell surface. Conversely the truncated splicing variant of RAET1G2 was shown to encode a soluble molecule that could be secreted from cells. Secreted RAET1G2 was shown to downregulate NKG2D receptor expression on NK cells and hence may represent a novel tumour immune evasion strategy. Conclusions/Significance: We demonstrate that the expression patterns of ULBP5RAET1G are very similar to the well-characterised NKG2D ligand, MICA. However the two isoforms of ULBP5/RAET1G have very different cellular localisations that are likely to reflect unique functionality

Unique genomic profile of fibrolamellar hepatocellular carcinoma

BACKGROUND & AIMS: Fibrolamellar hepatocellular carcinoma (FLC) is a rare primary hepatic cancer that develops in children and young adults without cirrhosis. Little is known about its pathogenesis, and it can be treated only with surgery. We performed an integrative genomic analysis of a large series of patients with FLC to identify associated genetic factors. METHODS: By using 78 clinically annotated FLC samples, we performed whole-transcriptome (n = 58), single-nucleotide polymorphism array (n = 41), and next-generation sequencing (n = 48) analyses; we also assessed the prevalence of the DNAJB1-PRKACA fusion transcript associated with this cancer (n = 73). We performed class discovery using non-negative matrix factorization, and functional annotation using gene-set enrichment analyses, nearest template prediction, ingenuity pathway analyses, and immunohistochemistry. The genomic identification of significant targets in a cancer algorithm was used to identify chromosomal aberrations, MuTect and VarScan2 were used to identify somatic mutations, and the random survival forest was used to determine patient prognoses. Findings were validated in an independent cohort. RESULTS: Unsupervised gene expression clustering showed 3 robust molecular classes of tumors: the proliferation class (51% of samples) had altered expression of genes that regulate proliferation and mammalian target of rapamycin signaling activation; the inflammation class (26% of samples) had altered expression of genes that regulate inflammation and cytokine enriched production; and the unannotated class (23% of samples) had a gene expression signature that was not associated previously with liver tumors. Expression of genes that regulate neuroendocrine function, as well as histologic markers of cholangiocytes and hepatocytes, were detected in all 3 classes. FLCs had few copy number variations; the most frequent were focal amplification at 8q24.3 (in 12.5% of samples), and deletions at 19p13 (in 28% of samples) and 22q13.32 (in 25% of samples). The DNAJB1-PRKACA fusion transcript was detected in 79% of samples. FLC samples also contained mutations in cancer-related genes such as BRCA2 (in 4.2% of samples), which are uncommon in liver neoplasms. However, FLCs did not contain mutations most commonly detected in liver cancers. We identified an 8-gene signature that predicted survival of patients with FLC. CONCLUSIONS: In a genomic analysis of 78 FLC samples, we identified 3 classes based on gene expression profiles. FLCs contain mutations and chromosomal aberrations not previously associated with liver cancer, and almost 80% contain the DNAJB1-PRKACA fusion transcript. By using this information, we identified a gene signature that is associated with patient survival time

Gene expression profiling of meningiomas: current status after a decade of microarray-based transcriptomic studies

Purpose This article provides a review of the transcriptomic expression profiling studies that have been performed on meningiomas so far. We discuss some future prospects and challenges ahead in the field of gene expression profiling. Methods We performed a systematic search in the PubMed and EMBASE databases in May 2010 using the following search terms alone or in combination: “meningioma”, “microarray analysis”, “oligonucleotide array sequence analysis”, or “gene expression profiling”. Only original research articles in English that had used RNA hybridized to high-resolution microarray chips to generate gene expression profiles were included. Results We identified 13 articles matching the inclusion criteria. All studies had been performed during the last decade. Conclusions The main results of the studies can be grouped in three categories: (1) several groups have identified meningioma-specific genes and genes associated with the three WHO grades, and the main histological subtypes of grade I meningiomas; (2) one publication has shown that the general transcription profile of samples of all WHO grades differs in vivo and in vitro; (3) one report provides evidence that microarray technology can be used in an automated fashion to classify tumors. Due to lack of consensus on how microarray data are presented, possible general trends found across the studies are difficult to extract. This could obstruct the discovery of important genes and pathways universally involved in meningioma biology

Spectrum of HNF1A Somatic Mutations in Hepatocellular Adenoma Differs From That in Patients With MODY3 and Suggests Genotoxic Damage

OBJECTIVE Maturity onset diabetes of the young type 3 (MODY3) is a consequence of heterozygous germline mutation in HNF1A. A subtype of hepatocellular adenoma (HCA) is also caused by biallelic somatic HNF1A mutations (H-HCA), and rare HCA may be related to MODY3. To better understand a relationship between the development of MODY3 and HCA, we compared both germline and somatic spectra of HNF1A mutations. RESEARCH DESIGN AND METHODS We compared 151 somatic HNF1A mutations in HCA with 364 germline mutations described in MODY3. We searched for genotoxic and oxidative stress features in HCA and surrounding liver tissue. RESULTS A spectrum of HNF1A somatic mutations significantly differed from the germline changes in MODY3. In HCA, we identified a specific hot spot at codon 206, nonsense and frameshift mutations mainly in the NH2-terminal part, and almost all amino acid substitutions were restricted to the POU-H domain. The high frequency of G-to-T tranversions, predominantly found on the nontranscribed DNA strand, suggested a genotoxic mechanism. However, no features of oxidative stress were observed in the nontumor liver tissue. Finally, in a few MODY3 patients with HNF1A germline mutation leading to amino acid substitutions outside the POU-H domain, we identified a different subtype of HCA either with a gp130 and/or CTNNB1 activating mutation. CONCLUSIONS Germline HNF1A mutations could be associated with different molecular subtypes of HCA. H-HCA showed mutations profoundly inactivating hepatocyte nuclear factor-1α function; they are associated with a genotoxic signature suggesting a specific toxicant exposure that could be associated with genetic predisposition

Clear and independent associations of several HLA-DRB1 alleles with differential antibody responses to hepatitis B vaccination in youth

To confirm and refine associations of human leukocyte antigen (HLA) genotypes with variable antibody (Ab) responses to hepatitis B vaccination, we have analyzed 255 HIV-1 seropositive (HIV+) youth and 80 HIV-1 seronegatives (HIV−) enrolled into prospective studies. In univariate analyses that focused on HLA-DRB1, -DQA1, and -DQB1 alleles and haplotypes, the DRB1*03 allele group and DRB1*0701 were negatively associated with the responder phenotype (serum Ab concentration ≥ 10 mIU/mL) (P = 0.026 and 0.043, respectively). Collectively, DRB1*03 and DRB1*0701 were found in 42 (53.8%) out of 78 non-responders (serum Ab <10 mIU/mL), 65 (40.6%) out of 160 medium responders (serum Ab 10–1,000 mIU/mL), and 27 (27.8%) out of 97 high responders (serum Ab >1,000 mIU/mL) (P < 0.001 for trend). Meanwhile, DRB1*08 was positively associated with the responder phenotype (P = 0.010), mostly due to DRB1*0804 (P = 0.008). These immunogenetic relationships were all independent of non-genetic factors, including HIV-1 infection status and immunodeficiency. Alternative analyses confined to HIV+ youth or Hispanic youth led to similar findings. In contrast, analyses of more than 80 non-coding, single nucleotide polymorphisms within and beyond the three HLA class II genes revealed no clear associations. Overall, several HLA-DRB1 alleles were major predictors of differential Ab responses to hepatitis B vaccination in youth, suggesting that T-helper cell-dependent pathways mediated through HLA class II antigen presentation are critical to effective immune response to recombinant vaccines

Human Herpesvirus 8 (HHV8) Sequentially Shapes the NK Cell Repertoire during the Course of Asymptomatic Infection and Kaposi Sarcoma

The contribution of innate immunity to immunosurveillance of the oncogenic Human Herpes Virus 8 (HHV8) has not been studied in depth. We investigated NK cell phenotype and function in 70 HHV8-infected subjects, either asymptomatic carriers or having developed Kaposi's sarcoma (KS). Our results revealed substantial alterations of the NK cell receptor repertoire in healthy HHV8 carriers, with reduced expression of NKp30, NKp46 and CD161 receptors. In addition, down-modulation of the activating NKG2D receptor, associated with impaired NK-cell lytic capacity, was observed in patients with active KS. Resolution of KS after treatment was accompanied with restoration of NKG2D levels and NK cell activity. HHV8-latently infected endothelial cells overexpressed ligands of several NK cell receptors, including NKG2D ligands. The strong expression of NKG2D ligands by tumor cells was confirmed in situ by immunohistochemical staining of KS biopsies. However, no tumor-infiltrating NK cells were detected, suggesting a defect in NK cell homing or survival in the KS microenvironment. Among the known KS-derived immunoregulatory factors, we identified prostaglandin E2 (PGE2) as a critical element responsible for the down-modulation of NKG2D expression on resting NK cells. Moreover, PGE2 prevented up-regulation of the NKG2D and NKp30 receptors on IL-15-activated NK cells, and inhibited the IL-15-induced proliferation and survival of NK cells. Altogether, our observations are consistent with distinct immunoevasion mechanisms that allow HHV8 to escape NK cell responses stepwise, first at early stages of infection to facilitate the maintenance of viral latency, and later to promote tumor cell growth through suppression of NKG2D-mediated functions. Importantly, our results provide additional support to the use of PGE2 inhibitors as an attractive approach to treat aggressive KS, as they could restore activation and survival of tumoricidal NK cells