Paving the path for implementation of clinical genomic sequencing globally: Are we ready?

Despite the emerging evidence in recent years, successful implementation of clinical genomic sequencing (CGS) remains limited and is challenged by a range of barriers. These include a lack of standardized practices, limited economic assessments for specific indications, limited meaningful patient engagement in health policy decision-making, and the associated costs and resource demand for implementation. Although CGS is gradually becoming more available and accessible worldwide, large variations and disparities remain, and reflections on the lessons learned for successful implementation are sparse.

The varied distribution and impact of RAS codon and other key DNA alterations across the translocation cyclin D subgroups in multiple myeloma.

We examined a set of 805 cases that underwent DNA sequencing using the FoundationOne Heme (F1H) targeted sequencing panel and gene expression profiling. Known and likely variant calls from the mutational data were analyzed for significant associations with gene expression defined translocation cyclin D (TC) molecular subgroups. The spectrum of KRAS, NRAS, and BRAF codon mutations varied across subgroups with NRAS mutations at Q61 codon being common in hyperdiploid (HRD) and t(11;14) myeloma while being rare in MMSET and MAF.

Explained Variance and Intraclass Correlation in a Two-Level AR(1) Model.

The total variance of a first-order autoregressive AR(1) time series is well known in time series literature. However, despite the increased use and interest in two-level AR(1) models, an equation for the total variance of these models does not exist. This paper presents an approximation of this total variance.

GATA-2 plays two functionally distinct roles during the ontogeny of hematopoietic stem cells.

GATA-2 is an essential transcription factor in the hematopoietic system that is expressed in hematopoietic stem cells (HSCs) and progenitors. Complete deficiency of GATA-2 in the mouse leads to severe anemia and embryonic lethality. The role of GATA-2 and dosage effects of this transcription factor in HSC development within the embryo and adult are largely unexplored.

A hampered chemoattractant-induced cytoskeletal rearrangement in granulocytes of patients with unexplained severe chronic and relapsing infections of the upper and lower airways. In vitro restoration by G-CSF exposure.

Granulocytes play a major role in host defense against bacterial infections. Severe inborn defects in granulocyte function are associated with fulminant bacterial infections in early childhood. Subtle disturbances in granulocyte function might contribute to an enhanced susceptibility to bacterial infections in adulthood.

Intracranial pressure, brain PCO2, PO2, and pH during hypo- and hyperventilation at constant mean airway pressure in pigs.

Objective: To evaluate in healthy, non-brain-traumatized animals the effects of hypo- and hyperventilation on intracranial pressure (ICP) and brain carbon dioxide, oxygen, and pH during the use of a ventilatory mode at constant mean airway pressure (MAwP).

Design And Setting: Prospective animal study in a university laboratory.

Subjects: Eight crossbred Landrace/Yorkshire pigs.

Rapid emergence of ciprofloxacin-resistant enterobacteriaceae containing multiple gentamicin resistance-associated integrons in a Dutch hospital.

In a hematology unit in the Netherlands, the incidence of ciprofloxacin-resistant Enterobacter cloacae and Escherichia coli increased from from 1996 to 1999. Clonal spread of single genotypes of both ciprofloxacin-resistant E. coli and Enterobacter cloacae from patient to patient was documented by pulsed-field gel electrophoresis and random amplification of polymorphic DNA.

The ARTS study (Arterial Revascularization Therapies Study).

The rising costs of health care have forced policy makers to make choices, and new treatments are increasingly assessed in terms of the balance between additional costs and additional effects. The recent recognition that stenting has a major and long-lasting effect enhancing balloon PTCA procedure has made it imperative to compare in patients with multivessel disease the standard surgical procedure with multiple stenting in a large scale multinational and multicentre approach (19 countries, 68 sites). Selection and inclusion of patients is based on a consensus of the cardiac surgeon and interventional cardiologist on equal 'treatability' of patients by both techniques with analysis of clinical follow-up (event-free survival) on the short (30 day), medium (1 year), and long-term (3 and 5 year) with analysis of cost-effectiveness and quality of life (EuroQol and SF-36).

Partial trisomy 4q and monosomy 9p resulting from a familial translocation t(4;9)(q27;p24) in a child with choanal atresia.

A male infant with a deletion of 9p and concomitant duplication of 4q: 46,XY, der(9)t(4;9)(q27;p24), is described. Parental chromosome analysis showed a balanced maternal translocation. To our knowledge, the above cytogenetic and clinical abnormalities have not been described previously.

Cross-lineage T cell receptor gene rearrangements occur in more than ninety percent of childhood precursor-B acute lymphoblastic leukemias: alternative PCR targets for detection of minimal residual disease.

A large series of 202 childhood precursor-B cell acute lymphoblastic leukemia (ALL) patients was analyzed by Southern blotting (SB) for cross-lineage rearrangements and/or deletions in the T cell receptor TCRB, TCRG and TCRD loci. In 93% (187/201) of the precursor-B-ALL patients one or more genes were rearranged and/or deleted. TCRB gene rearrangements were found in 35% (69/196), TCRG gene rearrangements in 59% (113/192), TCRD gene rearrangements in 55% (112/202), and isolated monoallelic or biallelic deletions of TCRD loci in 34% (68/202) of the cases.

Longitudinal evaluation of cytogenetic aberrations in prostatic cancer: tumours that recur in time display an intermediate genetic status between non-persistent and metastatic tumours.

Only limited data are available on chromosomes specifically involved in prostatic tumour progression. This study has evaluated the cytogenetic status of primary prostatic carcinomas, local tumour recurrences, and distant metastases, representing different time points in prostatic tumour progression. Interphase in situ hybridization (ISH) was applied with a set of (peri) centromeric DNA probes, specific for chromosomes 1, 7, 8 and Y, to routinely processed tissue sections of 73 tumour specimens from 32 patients.

Endoanal MRI of the anal sphincter complex: correlation with cross-sectional anatomy and histology.

The purpose of this study was to correlate the in vivo endoanal MRI findings of the anal sphincter with the cross-sectional anatomy and histology. Fourteen patients with rectal tumours were examined with a rigid endoanal MR coil before undergoing abdominoperineal resection. In addition, 12 cadavers were used to obtain cross-sectional anatomical sections.

Siblings of childhood cancer survivors: how does this "forgotten" group of children adjust after cessation of successful cancer treatment?

Siblings of childhood cancer patients are labelled the "forgotten children" because they experience significant psychosocial distress and are isolated from support systems inside and outside the family. This study investigates the late consequences of the cancer experience for siblings. 60 siblings of cancer survivors were compared with control subjects on measures of psychosocial adjustment.

Respiratory and haemodynamic effects of conventional volume controlled PEEP ventilation, pressure regulated volume controlled ventilation and low frequency positive pressure ventilation with extracorporeal carbon dioxide removal in pigs with acute ARDS.

The purpose of this study was to evaluate whether any benefit of low frequency positive pressure ventilation with extracorporeal carbon dioxide removal (LFPPV-ECCO2R) existed over either volume controlled ventilation (VCV) with measured best-PEEP or pressure regulated volume controlled ventilation (PRVCV) with an inspiration/expiration (I/E) ratio of 4:1, with respect to arterial oxygenation, lung mechanics and haemodynamics, in acute respiratory failure. Fifteen adult pigs were used for the study. Respiratory failure was induced by surfactant depletion by repeated lung lavage.

The current endothelin receptor classification: time for reconsideration?

The possible involvement of endothelins in a variety of diseases has attracted the attention of many pharmacologists in search of a novel therapeutic approach. The rapid development of endothelin research has resulted in the molecular characterization and pharmacological recognition of ETA and ETB receptors, and in the development of compounds selective for these receptors. However, the characterization of receptors in various assays has shown that a number of effects are mediated by receptors that do not fit the present criteria for ETA or ETB receptors.

Aldehyde dehydrogenase involvement in a variant of the brown Norway rat acute myelocytic leukaemia (BNML) that acquired cyclophosphamide resistance in vivo.

The development of drug resistance is an important factor contributing to failure of chemotherapy in cancer patients. Cyclophosphamide (CP) is a cytostatic drug widely used in the treatment of haematological malignancies and solid tumours. Because CP requires bioactivation to become cytotoxic, an in vivo approach was chosen to generate a subline of the Brown Norway rat acute myelocytic leukaemia (BNML/CPR) highly resistant to CP to serve as a model to investigate the molecular mechanism(s) of cyclophosphamide resistance.

Air pollution, lagged effects of temperature, and mortality: The Netherlands 1979-87.

Objective: To explore whether the apparent low threshold for the mortality effects of air pollution could be the result of confounding.

Design: The associations between mortality and sulphur dioxide (SO2) were analysed taking into account potential confounding factors.

Setting: The Netherlands, 1979-87.

Activin is produced by rat Sertoli cells in vitro and can act as an autocrine regulator of Sertoli cell function.

The production of activin by Sertoli cells isolated from 21-day-old rats was studied using the mesoderm-inducing activity of activin on Xenopus laevis animal cap explants, immunoprecipitation and Western blotting. Furthermore, the effects of recombinant bovine activin-A on rat Sertoli cell aromatase activity and FSH and androgen receptor gene expression were examined. Animal cap explants from Xenopus laevis blastulas elongated after culture in conditioned medium of Sertoli cells cultured with or without ovine FSH or conditioned medium of the mouse Sertoli cell-derived TM4 cell line.

Leukocyte adhesion molecules on the vascular endothelium: their role in the pathogenesis of cardiovascular disease and the mechanisms underlying their expression.

It is well known that granulocytes increase infarct size after reperfusion of the ischemic myocardium, and that monocytes promote atherogenesis. Those cells are also believed to play a contributory role in pathogenesis of coronary restenosis as response to arterial injury during balloon angioplasty. The adhesion of those leukocytes to the vascular endothelium is a prerequisite for their recruitment and accumulation in the lesion.

Nitrofen-induced diaphragmatic hernias in rats: pulmonary antioxidant enzyme activities.

We developed an experimental rat model of congenital diaphragmatic hernia (CDH) to elucidate the etiology and pathogenesis of this serious congenital anomaly in humans and in particular to study the effects of a short period of artificial ventilation on the CDH lung in relation to antioxidant defense mechanisms. CDH was induced in about 60% of the offspring by maternal exposure to 2,4-dichlorophenyl-p-nitrophenylether (Nitrofen) during pregnancy. This herbicide resembles thyroid hormone in chemical structure.

Pre-operative anxiety variables as possible predictors of post-operative stay in hospital.

The extent to which measures of pre-operative anxiety predict post-operative hospital stay, over and above what is predicted by biographical, medical status and post-operative anxiety variables, was examined in 81 cholecystectomy patients. Hierarchical multiple regression analysis revealed that patients who were older, had lower health status and suffered from wound infection, had a longer post-operative hospital stay than others. None of the pre-operative anxiety measures had a significant incremental value in the prediction of the post-operative hospital stay.

Effect of antibiotics in fibrin sealant on healing colonic anastomoses in the rat.

In 90 rats a colonic anastomosis was constructed with 12 interrupted 7/0 polypropylene sutures. Group 1 (n = 30) served as a control group. In group 2 (n = 30) the anastomosis was sealed with fibrin adhesive and in group 3 (n = 30) a mixture of fibrin, clindamycin and cefotaxime was used.