Precision medicine in cancer: Challenges and recommendations from an EU-funded cervical cancer biobanking study

Background:Cervical cancer (CC) remains a leading cause of gynaecological cancer-related mortality worldwide. CC pathogenesis is triggered when human papillomavirus (HPV) inserts into the genome, resulting in tumour suppressor gene inactivation and oncogene activation. Collecting tumour and blood samples is critical for identifying these genetic alterations.Methods:BIO-RAIDs is the first prospective molecular profiling clinical study to include a substantial biobanking effort that used uniform high-quality standards and control of samples. In this European Union (EU)-funded study, we identified the challenges that were impeding the effective implementation of such a systematic and comprehensive biobanking effort.Results:The challenges included a lack of uniform international legal and ethical standards, complexities in clinical and molecular data management, and difficulties in determining the best technical platforms and data analysis techniques. Some difficulties were encountered by all investigators, while others affected only certain institutions, regions, or countries.Conclusions:The results of the BIO-RAIDs programme highlight the need to facilitate and standardise regulatory procedures, and we feel that there is also a need for international working groups that make recommendations to regulatory bodies, governmental funding agencies, and academic institutions to achieve a proficient biobanking programme throughout EU countries. This represents the first step in precision medicine

Discovery of a New Human Polyomavirus Associated with Trichodysplasia Spinulosa in an Immunocompromized Patient

The Polyomaviridae constitute a family of small DNA viruses infecting a variety of hosts. In humans, polyomaviruses can cause infections of the central nervous system, urinary tract, skin, and possibly the respiratory tract. Here we report the identification of a new human polyomavirus in plucked facial spines of a heart transplant patient with trichodysplasia spinulosa, a rare skin disease exclusively seen in immunocompromized patients. The trichodysplasia spinulosa-associated polyomavirus (TSV) genome was amplified through rolling-circle amplification and consists of a 5232-nucleotide circular DNA organized similarly to known polyomaviruses. Two putative “early” (small and large T antigen) and three putative “late” (VP1, VP2, VP3) genes were identified. The TSV large T antigen contains several domains (e.g. J-domain) and motifs (e.g. HPDKGG, pRb family-binding, zinc finger) described for other polyomaviruses and potentially involved in cellular transformation. Phylogenetic analysis revealed a close relationship of TSV with the Bornean orangutan polyomavirus and, more distantly, the Merkel cell polyomavirus that is found integrated in Merkel cell carcinomas of the skin. The presence of TSV in the affected patient's skin was confirmed by newly designed quantitative TSV-specific PCR, indicative of a viral load of 105 copies per cell. After topical cidofovir treatment, the lesions largely resolved coinciding with a reduction in TSV load. PCR screening demonstrated a 4% prevalence of TSV in an unrelated group of immunosuppressed transplant recipients without apparent disease. In conclusion, a new human polyomavirus was discovered and identified as the possible cause of trichodysplasia spinulosa in immunocompromized patients. The presence of TSV also in clinically unaffected individuals suggests frequent virus transmission causing subclinical, probably latent infections. Further studies have to reveal the impact of TSV infection in relation to other populations and diseases

Genetic markers and phosphoprotein forms of beta-catenin pβ-Cat552 and pβ-Cat675 are prognostic biomarkers of cervical cancer

BACKGROUND: Cervical cancer (CC) remains a leading cause of gynaecological cancer-related mortality world wide and constitutes the third most common malignancy in women. The RAIDs consortium (http://www. raids-fp7.eu/) conducted a prospective European study [BioRAIDs (NCT02428842)] with the objective to stratify CC patients for innovative treatments. A “metagene” of genomic markers in the PI3K pathway and epigenetic regulators had been previously associated with poor outcome [2]. METHODS: To detect new, more specific, targets for treatment of patients who resist standard chemo-radiation, a high-dimensional Cox model was applied to define dominant molecular variants, copy number variations, and reverse phase protein arrays (RPPA). FINDINGS: Survival analysis on 89 patients with all omics data available, suggested loss-of-function (LOF) or activating molecular alterations in nine genes to be candidate biomarkers for worse prognosis in patients treated by chemo-radiation while LOF of ATRX, MED13 as well as CASP8 were associated with better prognosis. When protein expression data by RPPA were factored in, the supposedly low molecula

CanScreen5, a global repository for breast, cervical and colorectal cancer screening programs

The CanScreen5 project is a global cancer screening data repository that aims to report the status and performance of breast, cervical and colorectal cancer screening programs using a harmonized set of criteria and indicators. Data collected mainly from the Ministry of Health in each country underwent quality validation and ultimately became publicly available through a Web-based portal. Until September 2022, 84 participating countries reported data for breast (n = 57), cervical (n = 75) or colorectal (n = 51) cancer screening programs in the repository. Substantial heterogeneity was observed regarding program organization and performance. Reported screening coverage ranged from 1.7% (Bangladesh) to 85.5% (England, United Kingdom) for breast cancer, from 2.1% (Côte d’Ivoire) to 86.3% (Sweden) for cervical cancer, and from 0.6% (Hungary) to 64.5% (the Netherlands) for colorectal cancer screening programs. Large variability was observed regarding compliance to further assessment of screening programs and detection rates reported for precancers and cancers. A concern is lack of data to estimate performance indicators across the screening continuum. This underscores the need for programs to incorporate quality assurance protocols supported by robust information systems. Program organization requires improvement in resource-limited settings, where screening is likely to be resource-stratified and tailored to country-specific situations.</p

How baseline, new-onset, and persistent depressive symptoms are associated with cardiovascular and non-cardiovascular mortality in incident patients on chronic dialysis

AbstractObjectiveDepressive symptoms are associated with mortality among patients on chronic dialysis therapy. It is currently unknown how different courses of depressive symptoms are associated with both cardiovascular and non-cardiovascular mortality.MethodsIn a Dutch prospective nation-wide cohort study among incident patients on chronic dialysis, 1077 patients completed the Mental Health Inventory, both at 3 and 12months after starting dialysis. Cox regression models were used to calculate crude and adjusted hazard ratios (HRs) for mortality for patients with depressive symptoms at 3months only (baseline only), at 12months only (new-onset), and both at 3 and 12months (persistent), using patients without depressive symptoms at 3 and 12months as reference group.ResultsDepressive symptoms at baseline only seemed to be a strong marker for non-cardiovascular mortality (HRadj 1.91, 95% CI 1.26–2.90), whereas cardiovascular mortality was only moderately increased (HRadj 1.41, 95% CI 0.85–2.33). In contrast, new-onset depressive symptoms were moderately associated with both cardiovascular (HRadj 1.66, 95% CI 1.06–2.58) and non-cardiovascular mortality (HRadj 1.46, 95% CI 0.97–2.20). Among patients with persistent depressive symptoms, a poor survival was observed due to both cardiovascular (HRadj 2.14, 95% CI 1.42–3.24) and non-cardiovascular related mortality (HRadj 1.76, 95% CI 1.20–2.59).ConclusionThis study showed that different courses of depressive symptoms were associated with a poor survival after the start of dialysis. In particular, temporary depressive symptoms at the start of dialysis may be a strong marker for non-cardiovascular mortality, whereas persistent depressive symptoms were associated with both cardiovascular and non-cardiovascular mortality

Heterozygous missense variants of LMX1A lead to nonsyndromic hearing impairment and vestibular dysfunction

Unraveling the causes and pathomechanisms of progressive disorders is essential for the development of therapeutic strategies. Here, we identified heterozygous pathogenic missense variants of LMX1A in two families of Dutch origin with progressive nonsyndromic hearing impairment (HI), using whole exome sequencing. One variant, c.721G > C (p.Val241Leu), occurred de novo and is predicted to affect the homeodomain of LMX1A, which is essential for DNA binding. The second variant, c.290G > C (p.Cys97Ser), predicted to affect a zinc-binding residue of the second LIM domain that is involved in protein–protein interactions. Bi-allelic deleterious variants of Lmx1a are associated with a complex phenotype in mice, including deafness and vestibular defects, due to arrest of inner ear development. Although Lmx1a mouse mutants demonstrate neurological, skeletal, pigmentation and reproductive system abnormalities, no syndromic features were present in the participating subjects of either family. LMX1A has previously been suggested as a candidate gene for intellectual disability, but our data do not support this, as affected subjects displayed normal cognition. Large variability was observed in the age of onset (a)symmetry, severity and progression rate of HI. About half of the affected individuals displayed vestibular dysfunction and experienced symptoms thereof. The late-onset progressive phenotype and the absence of cochleovestibular malformations on computed tomography scans indicate that heterozygous defects of LMX1A do not result in severe developmental abnormalities in humans. We propose that a single LMX1A wild-type copy is sufficient for normal development but insufficient for maintenance of cochleovestibular function. Alternatively, minor cochleovestibular developmental abnormalities could eventually lead to the progressive phenotype seen in the families

Not as civilizing as we thought: Coffee housen, sociability, and literary socialization in Amsterdam c. 168 - c. 1785

According to existing historiography the coffee house played an important role in the sociabilization of the late seventeenth- and the eighteenth-century bourgeoisie. The assumption in existing historiography is that the bourgeois went to the Dutch coffee houses to socialize, converse about political and ethical issues, and thus achieve personal growth. Sociabilization in the coffeehouses was encouraged by ‘literary socialization’: the conversations were spurred by the bourgeois’ reading of texts and introduced them to literary reading of these texts. In this article, we question this historiography for the case of Amsterdam between 1685 and 1785 by a closer investigation of both literary representations of coffee houses and judicial (notary) sources. Coffee houses often appear as scenes of gambling and violent encounters in the notary archives. Literary representations (plays, diaries) confirm a more dissolute and less civilizing character of the Amsterdam coffee house. Moreover, the number of coffee houses in Amsterdam diminished in the eighteenth century, and literary representations are almost completely absent after 1730. They do not appear in a typical bourgeois novel such as Sara Burgerhart. We conclude that coffee houses did not play the key role in literary socialization and sociabilization previously assumed

Usability of a Speech Centric Multimodal Directory Assistance Service

this paper the focus is on our experiments with a multimodal Directory Assistance service, as an example of a service that includes form-filling. This work is part of the IST project SMADA [1]. In the framework of the EURESCOM project MUST we are working on a mapbased application [2, 11]. The experience from the MUST project is used in the design of the experiments reported here, and in the interpretation of the result