A Population-Based Study Using Belgian Cancer Registry Data Supports Centralization of Esophageal Cancer Surgery in Belgium.

BACKGROUND: Esophageal cancer surgery outcomes benefit from higher hospital volumes. Despite the evidence, organization of national health care often is complex and depends on various factors. The volume-outcome results of this population-based study supported national health policy measures regarding concentration of esophageal resections in Belgium. METHODS: The Belgian Cancer Registry (BCR) database was linked to administrative data on cancer treatment. All Belgian patients with newly diagnosed esophageal cancer in 2008-2018 undergoing resection were allocated to the hospital at which surgery was performed. The study assessed hospital volume association with 90-day mortality and 5-year overall survival, classifying average annual hospital volume of resections as low (LV, <6), medium (MV, 6-19), or high (HV, ≥20) and as a continuous covariate in the regression models. RESULTS: The study included 4156 patients who had surgery in 79 hospitals (2 HV hospitals [37% of all surgeries], 12 MV hospitals [30% of all surgeries], and 65 LV hospitals [33% of all surgeries]). Adjusted 90-day mortality in HV hospitals was lower than in LV hospitals (odds ratio [OR], 0.37; 95% CI, 0.21-0.65; p = 0.001). Case-mix adjusted 5-year survival was superior in HV versus LV (hazard ratio [HR], 0.43; 95% CI, 0.31-0.60; p < 0.001). The continuous model demonstrated a lower 90-day mortality (OR, 0.40; 95% CI, 0.23-0.71; p = 0.002) and a superior 5-year survival (HR, 0.45; 95% CI, 0.33-0.63; p < 0.001) in hospitals with volumes of 40 or more resections annually. CONCLUSION: Population-based data from the BCR confirmed a strong volume-outcome association for esophageal resections. Improved 5-year survival in centers with annual volumes of 20 or more resections was driven mainly by the achievement of superior 90-day mortality. These findings supported centralization of esophageal resections in Belgium.

GSK3ß-SCFFBXW7α mediated phosphorylation and ubiquitination of IRF1 are required for its transcription-dependent turnover.

IRF1 (Interferon Regulatory Factor-1) is the prototype of the IRF family of DNA binding transcription factors. IRF1 protein expression is regulated by transient up-regulation in response to external stimuli followed by rapid degradation via the ubiquitin-proteasome system. Here we report that DNA bound IRF1 turnover is promoted by GSK3ß (Glycogen Synthase Kinase 3ß) via phosphorylation of the T181 residue which generates a phosphodegron for the SCF (Skp-Cul-Fbox) ubiquitin E3-ligase receptor protein Fbxw7α (F-box/WD40 7). This regulated turnover is essential for IRF1 activity, as mutation of T181 results in an improperly stabilized protein that accumulates at target promoters but fails to induce RNA-Pol-II elongation and subsequent transcription of target genes. Consequently, the anti-proliferative activity of IRF1 is lost in cell lines expressing T181A mutant. Further, cell lines with dysfunctional Fbxw7 are less sensitive to IRF1 overexpression, suggesting an important co-activator function for this ligase complex. As T181 phosphorylation requires both DNA binding and RNA-Pol-II elongation, we propose that this event acts to clear 'spent' molecules of IRF1 from transcriptionally engaged target promoters.

Cause of death for patients with breast cancer: discordance between death certificates and medical files, and impact on survival estimates.

BACKGROUND: Registration and coding of cause of death is prone to error since determining the exact underlying condition leading directly to death is challenging. In this study, causes of death from the death certificates were compared to patients' medical files interpreted by experts at University Hospitals Leuven (UHL), to assess concordance between sources and its impact on cancer survival assessment. METHODS: Breast cancer patients treated at UHL (2009-2014) (follow-up until December 31st 2016) were included in this study. Cause of death was obtained from death certificates and expert-reviewed medical files at UHL. Agreement was calculated using Cohen's kappa coefficient. Cause-specific survival (CSS) was calculated using the Kaplan-Meier method and the relative survival probability (RS) using the Ederer II and Pohar Perme method. RESULTS: A total of 2862 patients, of whom 354 died, were included. We found an agreement of 84.7% (kappa-value of 0.69 (95% C.I.: 0.62-0.77)) between death certificates and medical files. Death certificates had 10.7% false positive and 4.5% false negative rates. However, five-year CSS and RS measures were comparable for both sources. CONCLUSION: For breast cancer patients included in our study, fair agreement of cause of death was seen between death certificates and medical files with similar CSS and RS estimations.

Heteromerization of Arabidopsis Kv channel alpha-subunits: Data and prospects.

Potassium translocation in plants is accomplished by a large variety of transport systems. Most of the available molecular information on these proteins concerns voltage-gated potassium channels (Kv channels). The Arabidopsis genome comprises nine genes encoding alpha-subunits of Kv channels. Based on knowledge of their animal homologues, and on biochemical investigations, it is broadly admitted that four such polypeptides must assemble to yield a functional Kv channel. The intrinsic functional properties of Kv channel alpha-subunits have been described by expressing them in suitable heterologous contexts where homo-tetrameric channels could be characterized. However, due to the high similarity of both the polypeptidic sequence and the structural scheme of Kv channel alpha-subunits, formation of heteromeric Kv channels by at least two types of alpha-subunits is conceivable. Several examples of such heteromeric plant Kv channels have been studied in heterologous expression systems and evidence that heteromerization actually occurs in planta has now been published. It is therefore challenging to uncover the physiological role of this heteromerization. Fine tuning of Kv channels by heteromerisation could be relevant not only to potassium transport but also to electrical signaling within the plant.

Increased functional diversity of plant K+ channels by preferential heteromerization of the shaker-like subunits AKT2 and KAT2.

Assembly of plant Shaker subunits as heterotetramers, increasing channel functional diversity, has been reported. Here we focus on a new interaction, between AKT2 and KAT2 subunits. The assembly as AKT2/KAT2 heterotetramers is demonstrated by (i) a strong signal in two-hybrid tests with intracytoplasmic C-terminal regions, (ii) the effect of KAT2 on AKT2 subunit targeting in tobacco cells, (iii) the complete inhibition of AKT2 currents by co-expression with a dominant-negative KAT2 subunit in Xenopus oocytes, and reciprocally, and (iv) the appearance, upon co-expression of wild-type AKT2 and KAT2 subunits, of new channel functional properties that cannot be explained by the co-existence of two kinds of homotetrameric channels. In particular, the instantaneous current, characteristic of AKT2, displayed new functional features when compared with those of AKT2 homotetramers: activation by external acidification (instead of inhibition) and weak inhibition by calcium. Single channel current measurements in oocytes co-expressing AKT2 and KAT2 revealed a strong preference for incorporation of subunits into heteromultimers and a diversity of individual channels. In planta, these new channels, which may undergo specific regulations, are likely to be formed in guard cells and in the phloem, where they could participate in the control of membrane potential and potassium fluxes.