Imatinib mesylate induces quiescence in gastrointestinal stromal tumor cells through the CDH1-SKP2-p27Kip1 signaling axis

Gastrointestinal stromal tumors (GIST) are caused by activating mutations in the KIT or platelet-derived growth factor receptor alpha receptor tyrosine kinase genes. Approximately 85% of GIST patients treated with imatinib mesylate achieve disease stabilization, however, often in the presence of residual tumor masses. Complete remissions are rare and a substantial proportion of patients develop resistance to imatinib. Our study was designed to determine whether imatinib-associated responses may account for these clinical findings. We report here that imatinib stimulates cellular quiescence in a proportion of GIST cells as evidenced by up-regulation of the CDK inhibitor p27(Kip1), loss of cyclin A, and reduced BrdUrd incorporation. Mechanistically, these events are associated with an imatinib-induced modulation of the APC/CDH1 signaling axis. Specifically, we provide evidence that imatinib down-regulates SKP2 and that this event is associated with increased nuclear CDH1, an activator of the APC that has been shown to regulate SKP2 stability. We also show that those GIST cells that do not undergo apoptosis in response to imatinib overexpress nuclear p27(Kip1), indicating that they have withdrawn from the cell cycle and are quiescent. Lastly, we provide evidence that a fraction of primary GISTs with high SKP2 expression levels may have an increased risk of disease progression. Taken together, our results support a model in which GIST cells that do not respond to imatinib by apoptosis are removed from the proliferative pool by entering quiescence through modulation of the APC/CDH1-SKP2-p27(Kip1) signaling axis. These results encourage further studies to explore compounds that modulate this pathway as antitumor agents in GISTs.     

Evaluation of Current Methods for Detection of Staphylococci with Reduced Susceptibility to Glycopeptides

The sensitivity and specificity of seven methods (agar dilution, broth microdilution, Etest at 0.5 and 2.0 McFarland (McF) inocula, two agar screening methods, and population studies [PS]) were evaluated in a double-blind study involving 284 methicillin-resistant Staphylococcus aureus (MRSA) strains and 45 Staphylococcus strains with reduced susceptibilities to vancomycin (SRSV). The results were compared to the population analysis profile-area under the curve ratio method (PAP-AUC ratio compared to that of Mu3) as described by Wootton et al. The agar screening method using brain heart infusion agar (6 microg of vancomycin per ml) gave a sensitivity of 22% and a specificity of 97%. A similar method using Mueller-Hinton agar (5 microg of vancomycin per ml) gave a sensitivity of 20% and a specificity of 99%. The PS method detected 34 false positives (12%) and gave a sensitivity of 71% and a specificity of 88%. Etest using 0.5 and 2.0 McF inocula gave sensitivities and specificities of 82 and 93% and of 96 and 97%, respectively. The best Etest interpretative criteria for the 2.0 McF inoculum was > or =8 mg of vancomycin per liter and > or =8 microg teicoplanin per ml or > or =12 microg of teicoplanin per ml. The direct colony suspension inoculum for this method was found to be equally accurate in detecting (hetero-)glycopeptide-intermediate S. aureus compared to the overnight broth inoculum preparation method. Agar dilution and broth microdilution using the NCCLS breakpoint criteria for vancomycin gave sensitivities and specificities of 20 and 100% and of 11 and 100%, respectively. Using the Etest with a 2.0 McF inoculum, six different media were assessed against a selection of SRSV (n = 48) and MRSA (n = 12). Brain heart infusion agar yielded the highest sensitivity and specificity values: 88 and 88%, respectively.     

Insufficient classification of anaemia in general practice: a Danish register-based observational study

BackgroundAnaemia can be a pointer of underlying severe disease, including undiagnosed malignancy. Subsequent blood tests are essential to classify the anaemia into subtypes and to facilitate targeted diagnostic investigation to ensure timely diagnosis of underlying disease.ObjectiveWe aimed to describe and classify anaemia based on laboratory tests from patients with new-onset anaemia detected in general practice. An additional aim was to analyse associations between patient characteristics and unclassified anaemia (not classifiable according to an algorithm).DesignPopulation-based cross-sectional study.SettingDanish general practice.SubjectsA total of 62,731 patients (age: 40–90 years) with new-onset anaemia were identified in Danish laboratory information systems and nationwide registries, and data were obtained for 2014–2018.Main outcome measuresWe measured the proportion of patients classified into subtypes of anaemia based on blood tests requested by general practitioners within 31 days of the anaemia index date.ResultsOf the 62,731 patients with new-onset anaemia, we identified unclassified anaemia in 78.9% (95% confidence interval (CI): 77.3–80.5) of men and 65.1% (CI: 63.4–66.9) of women. The likelihood of unclassified anaemia increased with age, increasing comorbidity and decreasing severity of anaemia.ConclusionThe majority of patients with new-onset anaemia could not be classified through a simple algorithm due to missing blood tests, which highlights a potential missed opportunity for diagnosis. Standardised laboratory testing of patients with anaemia is warranted to ensure adequate follow-up and early detection of underlying severe disease.

KEY POINTS

• Anaemia can be a sign of malignancy, and anaemia classification is an important step in the diagnosis of underlying disorders.
• The majority of patients with anaemia could not be classified according to a simple algorithm due to missing blood tests.
• Some patient characteristics were associated with a high risk of unclassified anaemia: high age, high comorbidity, and severe anaemia.
• Standardised laboratory testing in patients with anaemia is needed to inform targeted diagnostic investigation to ensure timely diagnosis.

     

Pregnancy associated plasma protein A, a potential marker for vulnerable plaque in patients with non-ST-segment elevation acute coronary syndrome

Objectives

To describe the presence and time-related pattern of circulating pregnancy associated plasma protein A (PAPP-A) levels in patients with non ST-segment elevation acute coronary syndrome (NSTE-ACS).

Design and methods

Consecutively admitted patients (N = 573) with clinical signs of NSTE-ACS were included. Blood samples for analysis of PAPP-A were drawn at admission and every 6-8 h until levels of biomarkers of myocardial necrosis showed a consistent decrease.

Results

High-risk NSTE-ACS was diagnosed in 123 patients (23%). Significantly more patients with high-risk NSTE-ACS (63%) had detectable PAPP-A than did those with low-risk NSTE-ACS (49%) (P < 0.001). PAPP-A concentrations were significantly associated with typical angina at admission, significant ST-depressions on the ECG, multivessel disease and presence of high-risk NSTE-ACS.

Conclusion

PAPP-A seems to be a marker ischaemia both in patients with low- and high-risk NSTE-ACS, possibly due to the release of PAPP-A from the vulnerable plaque.     

Unplanned Start on Peritoneal Dialysis Right after PD Catheter Implantation for Older People with End-Stage Renal Disease

Unplanned start on dialysis remains a major problem for the dialysis community worldwide. Late-referred patients with end-stage renal disease (ESRD) and urgent need for dialysis are overrepresented among older people. These patients are particularly likely to be started on in-center hemodialysis (HD), with a temporary vascular access known to be associated with excess mortality and increased risks of potentially lethal complications such as bacteremia and central venous thrombosis or stenosis.The present paper describes in detail our program for unplanned start on automated peritoneal dialysis (APD) right after PD catheter implantation and summarizes our experiences with the program so far. Compared with planned start on PD after at least 2 weeks of break-in between PD catheter implantation and initiation of dialysis, unplanned start may be associated with a slight increased risk of mechanical complications but apparently no detrimental effect on mortality, peritonitis-free survival, or PD technique survival.In our opinion and experience, the risk of serious complications associated with the implantation and immediate use of a PD catheter is less than the risk of complications associated with unplanned start on HD with a temporary central venous catheter (CVC). Unplanned start on APD is a gentle, safe, and feasible alternative to unplanned start on HD with a temporary CVC that is also valid for the late-referred older patient with ESRD and urgent need for dialysis.     

Young adults’ medicine use for headache: The combined effect of socioeconomic position and perceived stress,and the contribution of sense of coherence

BackgroundOver-the-counter analgesic (OTCA) use is increasingly common and may have potential harmful side effects. The primary reason for using analgesics is headache symptoms. Whether OTCA use for headache is sensitive to psychosocial and social circumstances is an understudied topic.ObjectivesThe purpose of this study was to examine the combined effect of socioeconomic position (SEP) and perceived stress on OTCA use for headache. An additional objective was to determine whether sense of coherence (SOC) modifies the association.MethodsData derived from the cross-sectional “Danish Lifestyle and Medicine Use Study,” 2009. The study population consisted of men and women ages 25-44 years (n = 955). The dependent variable was OTCA use for headache within the past 14 days. The independent variables were SEP, perceived stress, and SOC. Gender, headache prevalence, and response method were included as covariates. Associations were examined by means of logistic regression analyses, and reported as odds ratios (ORs) with 95% confidence intervals.ResultsThe OR for OTCA use was 1.42 (0.94-2.14) (statistically nonsignificant) among participants with low SEP but no perceived stress (reference high SEP, no perceived stress), 2.09 (1.53-2.85) for participants with perceived stress and high SEP, and 2.65 (1.66-4.25) among participants with perceived stress and low SEP. In analysis, stratified by SOC associations were stronger among participants with low SOC than among those with high SOC.ConclusionsIndividuals exposed to both low SEP and high perceived stress have high odds for using OTCA for headache, apparently higher than participants only exposed to 1 of these factors. SOC may act as a buffer against the harmful effects of perceived stress and low SEP on OTCA use. Health care professionals and policymakers need to be aware of the sensitivity of OTCA use to psychosocial and social circumstances.