SKY1 is involved in cisplatin-induced cell kill in Saccharomyces cerevisiae, and inactivation of its human homologue, SRPK1, induces cisplatin resistance in a human ovarian carcinoma cell line

The therapeutic potential of cisplatin, one of the most active and widely used anticancer drugs, is severely limited by the occurrence of cellular resistance. In this study, using budding yeast Saccharomyces cerevisiae as a model organism to identify novel drug resistance genes, we found that disruption of the yeast gene SKY1 (serine/arginine-rich protein-specific kinase from budding yeast) by either transposon insertion or one-step gene replacement conferred cellular resistance to cisplatin. Heterologous expression of the human SKY1 homologue SRPK1 (serine/arginine-rich protein-specific kinase) in SKY1 deletion mutant yeast cells restored cisplatin sensitivity, suggesting that SRPK1 is a cisplatin sensitivity gene, the inactivation of which could lead to cisplatin resistance. Subsequently, we investigated the role of SRPK1 in cisplatin sensitivity and resistance in human ovarian carcinoma A2780 cells using antisense oligodeoxynucleotides. Treatment of A2780 cells with antisense oligodeoxynucleotides directed against the translation initiation site of SRPK1 led to down-regulation of SRPK1 protein and conferred a 4-fold resistance to cisplatin. The human SRPK1 gene has not been associated with drug resistance before. Our new findings strongly suggest that SRPK1 is involved in cisplatin-induced cell kill and indicate that SRPK1 might potentially be of importance for studying clinical drug resistance

Synchrotron emission from the T Tauri binary system V773 Tau A

The pre-main sequence binary system V773 Tau A shows remarkable flaring activity around periastron passage. Here, we present the observation of such a flare at a wavelength of 3 mm (90 GHz) performed with the Plateau de Bure Interferometer. We examine different possible causes for the energy losses responsible for the e-folding time of 2.3 hours of that flare. We exclude synchrotron, collisional, and inverse Compton losses because they are not consistent with observational constraints, and we propose that the fading of the emission is due to the leakage of electrons themselves at each reflection between the two mirror points of the magnetic structure partially trapping them. The magnetic structure compatible with both our leakage model and previous observations is that of a helmet streamer that, as in the solar case, can occur at the top of the X-ray-emitting, stellar-sized coronal loops of one of the stars. The streamer may extend up to 20 R and interact with the corona of the other star at periastron passage, causing recurring flares. The inferred magnetic field strength at the two mirror points of the helmet streamer is in the range 0.12 - 125 G, and the corresponding Lorentz factor, gamma, of the partially trapped electrons is in the range 20 < gamma < 632. We therefore rule out that the emission could be of gyro-synchrotron nature: the derived high Lorentz factor proves that the nature of the emission at 90 GHz from this pre-main binary system is synchrotron radiation. Based on observations carried out with the IRAM Plateau de Bure Interferometer. IRAM is supported by INSU/CNRS (France), MPG (Germany), and IGN (Spain).Comment: 8 pages, 5 figures, A&A in pres

Does shade improve light interception efficiency? A comparison among seedlings from shade-tolerant and -intolerant temperate deciduous tree species

• Here, we tested two hypotheses: shading increases light interception efficiency (LIE) of broadleaved tree seedlings, and shade-tolerant species exhibit larger LIEs than do shade-intolerant ones. The impact of seedling size was taken into account to detect potential size-independent effects on LIE. LIE was defined as the ratio of mean light intercepted by leaves to light intercepted by a horizontal surface of equal area. • Seedlings from five species differing in shade tolerance (Acer saccharum, Betula alleghaniensis, A. pseudoplatanus, B. pendula, Fagus sylvatica) were grown under neutral shading nets providing 36, 16 and 4% of external irradiance. Seedlings (1- and 2-year-old) were three-dimensionally digitized, allowing calculation of LIE. • Shading induced dramatic reduction in total leaf area, which was lowest in shade-tolerant species in all irradiance regimes. Irradiance reduced LIE through increasing leaf overlap with increasing leaf area. There was very little evidence of significant size-independent plasticity of LIE. • No relationship was found between the known shade tolerance of species and LIE at equivalent size and irradiance

Working time flexibility components and working time regimes in Europe: using company-level data across 21 countries

Working time ?exibility comprises a wide variety of arrangements, from part-time, overtime, to long-term leaves. Theoretical approaches to grouping these arrangements have been developed, but empirical underpinnings are rare. This article investigates the bundles that can be found for various ?exible working time arrangements, using the Establishment Survey on Working Time and Work–Life Balance, 2004/2005, covering 21 EU member states and 13 industries. The results from the factor analyses con?rmed that working time arrangements can be grouped into two bundles, one for the employee-centred arrangements and second for the employer-centred arrangements, and that these two bundles are separate dimensions.Wealso tested the stability of the factor analysisoutcome, showing that although we ?nd some deviations from the pan-Europe and pan-industry outcome, the naming of the components as ?exibility for employees and ?exibility for employers can be considered rather stable. Lastly, we ?nd three country clusters for the 21 European countries using the bundle approach. The ?rst group includes the Northern European countries along side Poland and Czech Republic, the second group the continental European countries with UK and Ireland, and lastly, the southern European countries with Hungary and Slovenia

Assessing quality of hepato-pancreato-biliary surgery: nationwide benchmarking

Background: Clinical auditing is a powerful tool to evaluate and improve healthcare. Deviations from the expected quality of care are identified by benchmarking the results of individual hospitals using national averages. This study aimed to evaluate the use of quality indicators for benchmarking hepato-pancreato-biliary (HPB) surgery and when outlier hospitals could be identified. Methods: A population-based study used data from two nationwide Dutch HPB audits (DHBA and DPCA) from 2014 to 2021. Sample size calculations determined the threshold (in percentage points) to identify centres as statistical outliers, based on current volume requirements (annual minimum of 20 resections) on a two-year period (2020–2021), covering mortality rate, failure to rescue (FTR), major morbidity rate and textbook/ideal outcome (TO) for minor liver resection (LR), major LR, pancreaticoduodenectomy (PD) and distal pancreatectomy (DP). Results: In total, 10 963 and 7365 patients who underwent liver and pancreatic resection respectively were included. Benchmark and corresponding range of mortality rates were 0.6% (0 −3.2%) and 3.3% (0–16.7%) for minor and major LR, and 2.7% (0–7.0%) and 0.6% (0–4.2%) for PD and DP respectively. FTR rates were 5.4% (0–33.3%), 14.2% (0–100%), 7.5% (1.6%–28.5%) and 3.1% (0–14.9%). For major morbidity rate, corresponding rates were 9.8% (0–20.5%), 28.1% (0–47.1%), 36% (15.8%–58.3%) and 22.3% (5.2%–46.1%). For TO, corresponding rates were 73.6% (61.3%–94.4%), 54.1% (35.3–100), 46.8% (25.3%–59.4%) and 63.3% (30.7%–84.6%). Mortality rate thresholds indicating a significant outlier were 8.6% and 15.4% for minor and major LR and 14.2% and 8.6% for PD and DP. For FTR, these thresholds were 17.9%, 31.6%, 22.9% and 15.0%. For major morbidity rate, these thresholds were 26.1%, 49.7%, 57.9% and 52.9% respectively. For TO, lower thresholds were 52.5%, 32.5%, 25.8% and 41.4% respectively. Higher hospital volumes decrease thresholds to detect outliers. Conclusion: Current event rates and minimum volume requirements per hospital are too low to detect any meaningful between hospital differences in mortality rate and FTR. Major morbidity rate and TO are better candidates to use for benchmarking

Assessing quality of hepato-pancreato-biliary surgery: nationwide benchmarking

Background: Clinical auditing is a powerful tool to evaluate and improve healthcare. Deviations from the expected quality of care are identified by benchmarking the results of individual hospitals using national averages. This study aimed to evaluate the use of quality indicators for benchmarking hepato-pancreato-biliary (HPB) surgery and when outlier hospitals could be identified. Methods: A population-based study used data from two nationwide Dutch HPB audits (DHBA and DPCA) from 2014 to 2021. Sample size calculations determined the threshold (in percentage points) to identify centres as statistical outliers, based on current volume requirements (annual minimum of 20 resections) on a two-year period (2020–2021), covering mortality rate, failure to rescue (FTR), major morbidity rate and textbook/ideal outcome (TO) for minor liver resection (LR), major LR, pancreaticoduodenectomy (PD) and distal pancreatectomy (DP). Results: In total, 10 963 and 7365 patients who underwent liver and pancreatic resection respectively were included. Benchmark and corresponding range of mortality rates were 0.6% (0 −3.2%) and 3.3% (0–16.7%) for minor and major LR, and 2.7% (0–7.0%) and 0.6% (0–4.2%) for PD and DP respectively. FTR rates were 5.4% (0–33.3%), 14.2% (0–100%), 7.5% (1.6%–28.5%) and 3.1% (0–14.9%). For major morbidity rate, corresponding rates were 9.8% (0–20.5%), 28.1% (0–47.1%), 36% (15.8%–58.3%) and 22.3% (5.2%–46.1%). For TO, corresponding rates were 73.6% (61.3%–94.4%), 54.1% (35.3–100), 46.8% (25.3%–59.4%) and 63.3% (30.7%–84.6%). Mortality rate thresholds indicating a significant outlier were 8.6% and 15.4% for minor and major LR and 14.2% and 8.6% for PD and DP. For FTR, these thresholds were 17.9%, 31.6%, 22.9% and 15.0%. For major morbidity rate, these thresholds were 26.1%, 49.7%, 57.9% and 52.9% respectively. For TO, lower thresholds were 52.5%, 32.5%, 25.8% and 41.4% respectively. Higher hospital volumes decrease thresholds to detect outliers. Conclusion: Current event rates and minimum volume requirements per hospital are too low to detect any meaningful between hospital differences in mortality rate and FTR. Major morbidity rate and TO are better candidates to use for benchmarking

Short-term postoperative outcomes after liver resection in the elderly patient:a nationwide population-based study

BACKGROUND: Liver resection is high-risk surgery in particular in elderly patients. The aim of this study was to explore postoperative outcomes after liver resection in elderly patients. METHODS: In this nationwide study, all patients who underwent liver resection for primary and secondary liver tumours in the Netherlands between 2014 and 2019 were included. Age groups were composed as younger than 70 (70-), between 70 and 80 (septuagenarians), and 80 years or older (octogenarians). Proportion of liver resections per age group and 30-day major morbidity and 30-day mortality were assessed. RESULTS: In total, 6587 patients were included of whom 4023 (58.9%) were younger than 70, 2135 (32.4%) were septuagenarians and 429 (6.5%) were octogenarians. The proportion of septuagenarians increased during the study period (aOR:1.06, CI:1.02-1.09, p < 0.001). Thirty-day major morbidity was higher in septuagenarians (11%) and octogenarians (12%) compared to younger patients (9%, p = 0.049). Thirty-day mortality was higher in septuagenarians (4%) and octogenarians (4%) compared to younger patients (2%, p < 0.001). Cardiopulmonary complications occurred more frequently with higher age, liver-specific complications did not. Higher age was associated with higher 30-day morbidity and 30-day mortality in multivariable logistic regression. CONCLUSION: Thirty-day major morbidity and 30-day mortality are higher after liver resection in elderly patients, attributed mainly to non-surgical cardiopulmonary complications

Hospital variation and outcomes of simultaneous resection of primary colorectal tumour and liver metastases:a population-based study

BACKGROUND: The optimal treatment sequence for patients with synchronous colorectal liver metastases (CRLM) remains uncertain. This study aimed to assess factors associated with the use of simultaneous resections and impact on hospital variation. METHOD: This population-based study included all patients who underwent liver surgery for synchronous colorectal liver metastases between 2014 and 2019 in the Netherlands. Factors associated with simultaneous resection were identified. Short-term surgical outcomes of simultaneous resections and factors associated with 30-day major morbidity were evaluated. RESULTS: Of 2146 patients included, 589 (27%) underwent simultaneous resection in 28 hospitals. Simultaneous resection was associated with age, sex, BMI, number, size and bilobar distribution of CRLM, and administration of preoperative chemotherapy. More minimally invasive and minor resections were performed in the simultaneous group. Hospital variation was present (range 2.4%-83.3%) with several hospitals performing simultaneous procedures more and less frequently than expected. Simultaneous resection resulted in 13% 30-day major morbidity, and 1% mortality. ASA classification ≥3 was independently associated with higher 30-day major morbidity after simultaneous resection (aOR 1.97, CI 1.10-3.42, p = 0.018). CONCLUSION: Distinctive patient and tumour characteristics influence the choice for simultaneous resection. Remarkable hospital variation is present in the Netherlands

Ruthenium polypyridyl complexes and their modes of interaction with DNA : is there a correlation between these interactions and the antitumor activity of the compounds?

Various interaction modes between a group of six ruthenium polypyridyl complexes and DNA have been studied using a number of spectroscopic techniques. Five mononuclear species were selected with formula [Ru(tpy) L1L2](2-n)?, and one closely related dinuclear cation of formula [{Ru(apy)(tpy)}2{l-H2N(CH2)6NH2}]4?. The ligand tpy is 2,20:60,200-terpyridine and the ligand L1 is a bidentate ligand, namely, apy (2,20-azobispyridine), 2-phenylazopyridine, or 2-phenylpyridinylmethylene amine. The ligand L2 is a labile monodentate ligand, being Cl-, H2O, or CH3CN. All six species containing a labile L2 were found to be able to coordinate to the DNA model base 9-ethylguanine by 1H NMR and mass spectrometry. The dinuclear cationic species, which has no positions available for coordination to a DNA base, was studied for comparison purposes. The interactions between a selection of four representative complexes and calf-thymus DNA were studied by circular and linear dichroism. To explore a possible relation between DNA-binding ability and toxicity, all compounds were screened for anticancer activity in a variety of cancer cell lines, showing in some cases an activity which is comparable to that of cisplatin. Comparison of the details of the compound structures, their DNA binding, and their toxicity allows the exploration of structure–activity relationships that might be used to guide optimization of the activity of agents of this class of compounds

Population-based study on practice variation regarding preoperative systemic chemotherapy in patients with colorectal liver metastases and impact on short-term outcomes

Introduction: Definitions regarding resectability and hence indications for preoperative chemotherapy vary. Use of preoperative chemotherapy may influence postoperative outcomes. This study aimed to assess the variation in use of preoperative chemotherapy for CRLM and related postoperative outcomes in the Netherlands. Materials and methods: All patients who underwent liver resection for CRLM in the Netherlands between 2014 and 2018 were included from a national database. Case-mix factors contributing to the use of preoperative chemotherapy, hospital variation and postoperative outcomes were assessed using multivariable logistic regression. Postoperative outcomes were postoperative complicated course (PCC), 30-day morbidity and 30-day mortality. Results: In total, 4469 patients were included of whom 1314 patients received preoperative chemotherapy and 3155 patients did not. Patients receiving chemotherapy were significantly younger (mean age (+SD) 66.3 (10.4) versus 63.2 (10.2) p < 0.001) and had less comorbidity (Charlson scores 2+ (24% versus 29%, p = 0.010). Unadjusted hospital variation concerning administration of preoperative chemotherapy ranged between 2% and 55%. After adjusting for case-mix factors, three hospitals administered significantly more preoperative chemotherapy than expected and six administered significantly less preoperative chemotherapy than expected. PCC was 12.1%, 30-day morbidity was 8.8% and 30-day mortality was 1.5%. No association between preoperative chemotherapy and PCC (OR 1.24, 0.98–1.55, p = 0.065), 30-day morbidity (OR 1.05, 0.81–1.39, p = 0.703) or with 30-day mortality (OR 1.22, 0.75–2.09, p = 0.467) was found. Conclusion: Significant hospital variation in the use of preoperative chemotherapy for CRLM was present in the Netherlands. No association between postoperative outcomes and use of preoperative chemotherapy was found