Logarithmic expansion of LGR5+ cells in human colorectal cancer

Publication date: January 2018
Source:Cellular Signalling, Volume 42
Author(s): Maria Laura Martin, Zhaoshi Zeng, Mohammad Adileh, Adrian Jacobo, Christy Li, Efsevia Vakiani, Guoqiang Hua, Lixing Zhang, Adriana Haimovitz-Friedman, Zvi Fuks, Richard Kolesnick, Philip B. Paty
Stem cells of the small and large intestine are marked by expression of the Wnt target gene LGR5, a leucine-rich-repeat-containing G protein-coupled receptor. Previous studies reported increased expression of LGR5 in human colorectal cancer (CRC) compared to normal tissue either by immunohistochemistry or in situ hybridization (ISH). However, as these studies were semi-quantitative they did not provide a numerical estimate of the magnitude of this effect. While we confirm that LGR5⁺ cells are exclusively located at the base of normal human small and large intestinal crypts, representing approximately 6% of total crypt cells, we show this cell population is 10-fold expanded in all grades of CRC, representing as much as 70% of the cells of tumor crypt-like structures. This expansion of the LGR5 compartment coincides with maintenance of crypt-like glandular structure (adenomas, and well and moderately differentiated adenocarcinomas), and is reduced in poorly differentiated CRC, where crypt-like glandular architecture is lost, accompanied by reduced epithelial terminal differentiation. Altogether these results indicate that LGR5⁺ cell expansion is a hallmark of CRC tumorigenesis occurring during progression to adenoma, supporting CRC as a stem cell disease with implications for CRC therapy.



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Erratum to ‘Limitations and opportunities for immune checkpoint inhibitors in pediatric malignancies’ [Cancer Treat. Rev. 58C (2017) 22–33]

Publication date: Available online 21 October 2017
Source:Cancer Treatment Reviews
Author(s): Jeong A Park, Nai-Kong V. Cheung




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PFA-100-measured aspirin resistance is the predominant risk factor for hospitalized cardiovascular events in aspirin-treated patients: A 5-year cohort study

Summary

What is known and objective

Aspirin therapy is the clinical gold standard for the prevention of cardiovascular events. However, cardiovascular events still develop in some patients undergoing aspirin therapy. Many laboratory methods exist for measuring aspirin resistance. Using the platelet Function Analyzer (PFA)-100 system, we aimed to determine the effect of aspirin resistance on hospitalized cardiovascular events (hCVE) in a 5-year follow-up cohort. We also sought to determine the impact of aspirin resistance on the relationship between common cardiovascular risk factors and cardiovascular hospitalization.

Method

Aspirin resistance was evaluated in aspirin-treated patients from the outpatient department. A total of 465 patients during a 5-year follow-up period were included in this study. The primary endpoint of the study was hospitalization for any acute cardiovascular event. The prevalence and associated risk factors of acute cardiovascular events were evaluated.

Results and discussion

Aspirin resistance was prevalent in 91 (20.0%) of 465 patients. Prior hospitalization history of cardiovascular events was highly associated with aspirin resistance (P = .001). At the 5-year follow-up, cardiovascular events were found to have developed in 11 patients (8 stroke and 3 myocardial infarction) who exhibited aspirin resistance (12.1%) and in 9 (4 stroke and 5 myocardial infarction) patients who did not exhibit aspirin resistance (2.4%) (P < .001). At the 5-year follow-up, multivariate logistic regression analysis results showed a strong association between aspirin resistance and cardiovascular events (adjusted odds ratio 4.28; 95% CI: 1.64-11.20; P = .03).

What is new and conclusion

PFA-100 measurements of aspirin resistance correlate with hCVE, as evidenced by both the past medical history and the 5-year follow-up. The logistic regression analysis results showed that aspirin resistance plays a larger role in hospitalized cardiovascular disease than do other cardiovascular risk factors.

Aspirin resistance measured by PFA-100 highly correlate with past history of hospitalized cardiovascular events. After 5-year follow-up, the logistic regressive analysis results showed that aspirin resistance plays a larger role in hospitalized cardiovascular disease than do other cardiovascular risk factors.

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Deltona dental clinic worker charged with stealing $18,000

A receptionist at a Deltona dental clinic was arrested Friday night on charges she stole thousands of dollars in cash payments from the business' customers since the beginning of last year. Lucina Rodriguez, 52, of Deltona was charged with two counts of grand theft in the case, which involved 30 missing bank deposits totaling more than $18,000 in cash collected from customers at Dental Care of Deltona, according to a news release from the Volusia County Sheriff's Office.

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MEERCAT: MULTIPLEXED EFFICIENT CELL FREE EXPRESSION OF RECOMBINANT QconCATS FOR LARGE SCALE ABSOLUTE PROTEOME QUANTIFICATION [Research]

A major challenge in proteomics is the absolute accurate quantification of large numbers of proteins. QconCATs, artificial proteins that are concatenations of multiple standard peptides, are well established as an efficient means to generate standards for proteome quantification. Previously, QconCATs have been expressed in bacteria, but we now describe QconCAT expression in a robust, cell-free system. The new expression approach rescues QconCATs that previously were unable to be expressed in bacteria and can reduce the incidence of proteolytic damage to QconCATs. Moreover, it is possible to co-synthesise QconCATs in a highly-multiplexed translation reaction, co-expressing tens or hundreds of QconCATs simultaneously. By obviating bacterial culture and through the gain of high level multiplexing, it is now possible to generate tens of thousands of standard peptides in a matter of weeks, rendering absolute quantification of a complex proteome highly achievable in a reproducible, broadly deployable system.

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PreOp® Bedside Video Patient Education Participating Hospitals Project FreeTV

PreOp® Bedside Video Patient Education Participating Hospitals
Project FreeTv - http://ift.tt/2xWck9u
These hospitals are participating in various patient education and engagement platforms at the in-hospital bedside. These systems are also referred to as telehealth, cctv, patient engagement and more...

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Prenatal exposure to glycol ethers and cryptorchidism and hypospadias: a nested case-control study

Objectives

Glycol ethers (GE) are oxygenated solvents frequently found in occupational and consumer products. Some of them are well-known testicular and developmental animal toxicants. This study aims to evaluate the risk of male genital anomalies in association with prenatal exposure to GE using urinary biomarkers of exposure.

Methods

We conducted a case–control study nested in two joint mother–child cohorts (5303 pregnant women). Cases of cryptorchidism and hypospadias were identified at birth and confirmed during a 2-year follow-up period (n=14 cryptorchidism and n=15 hypospadias). Each case was matched to three randomly selected controls within the cohorts for region of inclusion and gestational age at urine sampling. Concentrations of five GE acidic metabolites were measured in spot maternal urine samples collected during pregnancy. ORs were estimated with multivariate conditional logistic regressions including a Firth's penalisation.

Results

Detection rates of urinary GE metabolites ranged from 8% to 93% and only two were sufficiently detected (>33%) in each cohort to be studied: methoxyacetic acid (MAA) and phenoxyacetic acid (PhAA). A significantly higher risk of hypospadias was associated with the highest tertile of exposure to MAA: OR (95% CI) 4.5(1.4 to 23.4). No association were observed with urinary concentration of PhAA, nor with the risk of cryptorchidism.

Conclusions

In view of the toxicological plausibility of our results, this study, despite its small sample size, raises concern about the potential developmental toxicity of MAA on the male genital system and calls for thorough identification of current sources of exposure to MAA.

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Impact of considering non-occupational radiation exposure on the association between occupational dose and solid cancer among French nuclear workers

Objectives

The French nuclear worker cohort allows for the assessment of cancer risk associated with occupational radiation exposure, but workers are also exposed to medical and environmental radiation which can be of the same order of magnitude. This study aims to examine the impact of non-occupational radiation exposures on the dose-risk analysis between occupational radiation exposure and cancer mortality.

Methods

The cohort included workers employed before 1995 for at least one year by CEA, AREVA NC or EDF and badge-monitored for external radiation exposure. Monitoring results were used to calculate occupational individual doses. Scenarios of work-related X-ray and environmental exposures were simulated. Poisson regression was used to quantify associations between occupational exposure and cancer mortality adjusting for non-occupational radiation exposure.

Results

The mean cumulative dose of external occupational radiation was 18.4 mSv among 59 004 workers. Depending on the hypotheses made, the mean cumulative work-related X-ray dose varied between 3.1 and 9.2 mSv and the mean cumulative environmental dose was around 130 mSv. The unadjusted excess relative rate of cancer per Sievert (ERR/Sv) was 0.34 (90% CI –0.44 to 1.24). Adjusting for environmental radiation exposure did not substantially modify this risk coefficient, but it was attenuated by medical exposure (ERR/Sv point estimate between 0.15 and 0.23).

Conclusions

Occupational radiation risk estimates were lower when adjusted for work-related X-ray exposures. Environmental exposures had a very slight impact on the occupational exposure risk estimates. In any scenario of non-occupational exposure considered, a positive but insignificant excess cancer risk associated with occupational exposure was observed.

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Pleural abnormalities in the Framingham Heart Study: prevalence and CT image features by Araki et al

The report by Araki et al is important for a number of reasons, most significantly that it is the first-ever study of pleural abnormalities potentially related to asbestos in a large, general population (the Framingham Heart Study (FHS) Third Generation cohort) that is based on chest CT scans rather than chest radiographs.1 Pleural abnormalities were reported to be present in 1.5% of the study population. A key conclusion of the study was that the prevalence of pleural abnormalities in the present study was significantly lower than what was observed in NHANES II (3.9%), and this was taken as evidence in support of reduced asbestos exposures in the decades since the National Health and Nutrition Examination Survey (NHANES) II data were collected in the period 1976–1980.2 It is important to note that the results of NHANES II were based on chest radiographs, while the results for the FHS cohort...

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Long-term follow-up for cancer incidence in a cohort of Danish firefighters

Objectives

To examine cancer incidence among Danish firefighters using several employment-related exposure subgroups.

Methods

A historical cohort of 9061 male Danish firefighters was established from collected personnel and membership records from employers and trade unions. Using the unique Danish personal identification number, information on additional previous employment, cancer and vital status was linked to members of the cohort from the Supplementary Pension Fund Register, the Danish Cancer Registry and the Danish Civil Registration System. SIRs were calculated for specific cancer types using rates for the general population, a sample of the working population and military employees, respectively.

Results

Compared with the selected reference groups, the overall observed incidence of cancer among the firefighters was at level with the expected (SIR 1.02, 95% CI 0.96 to 1.09 vs the general population). The SIR for colon cancer was consistently significantly reduced, while the slight excess seen for melanoma of the skin, prostate and testicular cancer compared with the general population was not reproduced using the military as reference.

Conclusions

Previous associations with melanoma of the skin, prostate and testicular cancer are supported by our main results. However, the increase in incidence of these cancers is not reproduced using the military as reference. Similarities in cancer profile for the firefighters and the military point to shared risk factors in either lifestyle or work environment.

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Industrial hog farming is associated with altered circulating immunological markers

Objectives

The previously observed inverse association between hog farming and risk of lung cancer in the Agricultural Health Study (AHS) has been attributed to endotoxin exposure, the levels of which are particularly high in industrial hog confinement facilities. We conducted an investigation to explore the potential biological mechanisms underlying this association, as well as other immunological changes associated with hog farming.

Methods

Serum immune marker levels were measured using a multiplexed bead-based assay in 61 active hog farmers and 61 controls matched on age, phlebotomy date and raising cattle. Both groups comprised non-smoking male AHS participants from Iowa. We compared natural log-transformed marker levels between hog farmers and controls using multivariate linear regression models.

Results

Circulating levels of macrophage-derived chemokine (CCL22), a chemokine previously implicated in lung carcinogenesis, were reduced among hog farmers (17% decrease; 95% CI –28% to –4%), in particular for those with the largest operations (>6000 hogs: 26% decrease; 95% CI –39% to –10%; p_trend=0.002). We also found that hog farmers had elevated levels of other immune markers, including macrophage inflammatory protein-3 alpha (MIP-3A/CCL20; 111% increase, 95% CI 19% to 273%), basic fibroblast growth factor (FGF-2; 93% increase, 95% CI 10% to 240%) and soluble interleukin-4 receptor (12% increase, 95% CI 1% to 25%), with particularly strong associations for MIP-3A/CCL20 and FGF-2 in winter.

Conclusions

These results provide insights into potential immunomodulatory mechanisms through which endotoxin or other exposures associated with hog farming may influence lung cancer risk, and warrant further investigation with more detailed bioaerosol exposure assessment.

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LGI1, CASPR2 and related antibodies: a molecular evolution of the phenotypes

Recent biochemical observations have helped redefine antigenic components within the voltage-gated potassium channel (VGKC) complex. The related autoantibodies may be now divided into likely pathogenic entities, which target the extracellular domains of leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein-like 2 (CASPR2), and species that target intracellular neuronal components and are likely non-pathogenic. This distinction has enhanced clinical practice as direct determination of LGI1 and CASPR2 antibodies offers optimal sensitivity and specificity. In this review, we describe and compare the clinical features associated with pathogenic LGI1 and CASPR2 antibodies, illustrate emerging laboratory techniques for antibody determination and describe the immunological mechanisms that may mediate antibody-induced pathology. We highlight marked clinical overlaps between patients with either LGI1 or CASPR2 antibodies that include frequent focal seizures, prominent amnesia, dysautonomia, neuromyotonia and neuropathic pain. Although occurring at differing rates, these commonalities are striking and only faciobrachial dystonic seizures reliably differentiate these two conditions. Furthermore, the coexistence of both LGI1 and CASPR2 antibodies in an individual occurs surprisingly frequently. Patients with either antibody respond well to immunotherapies, although systematic studies are required to determine the magnitude of the effect beyond placebo. Finally, data have suggested that CASPR2 and LGI1 modulation via genetic or autoimmune mechanisms may share common intermediate molecules. Taken together, the biochemical distinction of antigenic targets has led to important clinical advances for patient care. However, the striking syndrome similarities, coexistence of two otherwise rare antibodies and molecular insights suggest the VGKC complex may yet be a common functional effector of antibody action. Hence, we argue for a molecular evolution alongside a clinical and phenotypic re-evaluation.

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Balancing measures or a balanced accounting of improvement impact: a qualitative analysis of individual and focus group interviews with improvement experts in Scotland

Background

As quality improvement (QI) programmes have become progressively larger scale, the risks of implementation having unintended consequences are increasingly recognised. More routine use of balancing measures to monitor unintended consequences has been proposed to evaluate overall effectiveness, but in practice published improvement interventions hardly ever report identification or measurement of consequences other than intended goals of improvement.

Methods

We conducted 15 semistructured interviews and two focus groups with 24 improvement experts to explore the current understanding of balancing measures in QI and inform a more balanced accounting of the overall impact of improvement interventions. Data were analysed iteratively using the framework approach.

Results

Participants described the consequences of improvement in terms of desirability/undesirability and the extent to which they were expected/unexpected when planning improvement. Four types of consequences were defined: expected desirable consequences (goals); expected undesirable consequences (trade-offs); unexpected undesirable consequences (unpleasant surprises); and unexpected desirable consequences (pleasant surprises). Unexpected consequences were considered important but rarely measured in existing programmes, and an improvement pause to take stock after implementation would allow these to be more actively identified and managed. A balanced accounting of all consequences of improvement interventions can facilitate staff engagement and reduce resistance to change, but has to be offset against the cost of additional data collection.

Conclusion

Improvement measurement is usually focused on measuring intended goals, with minimal use of balancing measures which when used, typically monitor trade-offs expected before implementation. This paper proposes that improvers and leaders should seek a balanced accounting of all consequences of improvement across the life of an improvement programme, including deliberately pausing after implementation to identify and quantitatively or qualitatively evaluate any pleasant or unpleasant surprises.

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Night-time communication at Stanford University Hospital: perceptions, reality and solutions

Background

Resident work hour restrictions have led to the creation of the 'night float' to care for the patients of multiple primary teams after hours. These residents are often inundated with acute issues in the numerous patients they cover and are less able to address non-urgent issues that arise at night. Further, non-urgent pages may contribute to physician alarm fatigue and negatively impact patient outcomes.

Objective

To delineate the burden of non-urgent paging at night and propose solutions.

Methods

We performed a resident review and categorisation of 1820 pages to night floats between September 2014 and December 2014. Both attending and nursing review of 10% of pages was done and compared.

Results

Of reviewed pages, 62.1% were urgent and 27.7% were non-urgent. Attending review of random page samples correlated well with resident review. Common reasons for non-urgent pages were non-urgent patient status updates, low-priority order requests and non-critical lab values.

Conclusions

A significant number of non-urgent pages are sent at night. These pages likely distract from acute issues that arise at night and place an unnecessary burden on night floats. Both behavioural and systemic adjustments are needed to address this issue. Possible interventions include integrating low-priority messaging into the electronic health record system and use of charge nurses to help determine urgency of issues and batch non-urgent pages.

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Balancing the skills: the need for an improvement pyramid

Improvements in health services require a range of technical skills, but like all complex organisational tasks they also rely on the personal skills and attitudes of the staff carrying out the changes. That much is axiomatic.1 2 3 Less certain, but surely potentially helpful to front-line staff undertaking improvement initiatives, is ascertaining just what might be the right sets of skills needed for different kinds of improvement tasks in varying circumstances.4 5 6

Useful insights into the ways in which a range of organisational circumstances demand such skills were exposed when the Heath Foundation, an independent charity working to improve healthcare quality in the UK, funded our project to help local 'improvement groups' learn how to bring about specifically agreed developments, while simultaneously observing how the improvements worked out. By formatively evaluating the processes involved, the intention was to...

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Are quality improvement collaboratives effective? A systematic review

Background

Quality improvement collaboratives (QIC) have proliferated internationally, but there is little empirical evidence for their effectiveness.

Method

We searched Medline, Embase, CINAHL, PsycINFO and the Cochrane Library databases from January 1995 to December 2014. Studies were included if they met the criteria for a QIC intervention and the Cochrane Effective Practice and Organisation of Care (EPOC) minimum study design characteristics for inclusion in a review. We assessed study bias using the EPOC checklist and the quality of the reported intervention using a subset of SQUIRE 1.0 standards.

Results

Of the 220 studies meeting QIC criteria, 64 met EPOC study design standards for inclusion. There were 10 cluster randomised controlled trials, 24 controlled before-after studies and 30 interrupted time series studies. QICs encompassed a broad range of clinical settings, topics and populations ranging from neonates to the elderly. Few reports fully described QIC implementation and methods, intensity of activities, degree of site engagement and important contextual factors. By care setting, an improvement was reported for one or more of the study's primary effect measures in 83% of the studies (32/39 (82%) hospital based, 17/20 (85%) ambulatory care, 3/4 nursing home and a sole ambulance QIC). Eight studies described persistence of the intervention effect 6 months to 2 years after the end of the collaborative. Collaboratives reporting success generally addressed relatively straightforward aspects of care, had a strong evidence base and noted a clear evidence-practice gap in an accepted clinical pathway or guideline.

Conclusions

QICs have been adopted widely as an approach to shared learning and improvement in healthcare. Overall, the QICs included in this review reported significant improvements in targeted clinical processes and patient outcomes. These reports are encouraging, but most be interpreted cautiously since fewer than a third met established quality and reporting criteria, and publication bias is likely.

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Grant will help Headstart parents pay for children to visit dentist

Officials are very excited because this is the first year they've received a grant that's going to help their preschoolers with their initial screenings at the dentist office and even follow up appointments to fix those cavities or those fill-ins that they need to get. Tri-Cap Education and Volunteer Services Director Steve Marchand said the grant from the Dubois County Community Foundation will help increase the oral health of the headstart preschoolers they serve in Pike, Dubois, and Warrick Counties.

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Pasireotide for the Treatment of Refractory Hypoglycemia from Malignant Insulinoma

Abstract

Insulinomas are rare, usually solitary benign tumors. The presence of metastases defines malignant insulinomas⁽¹⁾. Medical therapy primarily treats symptomatic hypoglycemia, alleviates symptoms, and improves the quality of life in affected individuals. While diazoxide is used as first-line therapy, the incomplete response rate and complications associated with diazoxide provide a role for somatostatin analogues in difficult-to-treat hypoglycemia_.

This article is protected by copyright. All rights reserved.

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Long-Term Safety of Growth Hormone – A Combined Registry Analysis

Abstract

Objectives

Preliminary data from the French cohort of the Safety and Appropriateness of Growth hormone treatments in Europe (SAGhE) study raised concerns regarding the safety of recombinant human GH, suggesting that GH may increase mortality and incidence of stroke in patients treated during childhood for GH deficiency or short stature. We evaluated published safety data, focusing on mortality, neoplasms, cerebrovascular events and diabetes across a number of large-scale pharmaceutical company GH registries.

Design

A literature review was conducted using PubMed, EMBASE and Google Scholar to identify all relevant safety data from manufacturers' GH registries published between 1988 and April 2016. Results were hand-sorted to exclude non-relevant publications; bibliographic references from retrieved articles were evaluated for any additional references.

Results

The published data do not support an increased risk of mortality in children or adults treated with GH. There was no evidence of an increased risk of stroke, new malignancy, leukaemia, non-leukaemic extracranial tumours or recurrence of intracranial malignancy in patients without risk factors. The risk of a second neoplasm is increased, particularly if patients have received radiation therapy for a central nervous system tumour. There may be an increased risk of type 2 diabetes in GH-treated patients, but this appears to be confined to those with pre-existing risk factors.

Conclusions

Patients with risk factors for malignancy or type 2 diabetes should be treated with caution and monitored during follow-up, but current published data provide reassurance on the long-term safety profile of GH in patients receiving GH treatment.

This article is protected by copyright. All rights reserved.

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Utility of prehospital electrocardiogram characteristics as prognostic markers in out-of-hospital pulseless electrical activity arrests

Background

It is unclear if there are predictors of survival, including ECG characteristics, that can guide resuscitative efforts in pulseless electrical activity (PEA) cardiac arrests. We studied the predictive potential of presenting prehospital ECGs on survival for patients with out-of-hospital cardiac arrest (OHCA) with PEA.

Methods

We studied prehospital ECGs of patients with OHCA prospectively enrolled between June 2007 and November 2009 at the Ottawa/OPALS (Ontario Prehospital Advanced Life Support Study) site of the Resuscitation Outcomes Consortium PRIMED study (Prehospital Resuscitation using an IMpedance valve and Early versus Delayed analysis). We included adult non-traumatic OHCA with PEA rhythm where resuscitation was attempted. We measured HR, QRS interval and presence of P waves, and determined their impact on return of spontaneous circulation (ROSC) and survival to hospital discharge (SHD) using multivariate regression analysis.

Results

The demographic characteristics of the 332 included cases were the following: mean age 71.8, male 58.4%, SHD 5.4% and ROSC at ED arrival 26.5%. Survivors had similar HR (56.8 vs 52.0 beats per minute (bpm), p=0.53) and QRS intervals (128.7 vs 129.6 ms, p=0.95) compared with non-survivors. Prehospital ECG characteristics did not predict SHD or ROSC on multivariate analyses. Patients with initial HR <30 bpm had a 3.8% survival rate; those with both HR <30 bpm and QRS ≥120 ms had a 3.7% survival rate. Location of arrest predicted SHD (adjusted OR (AdjOR)=1.49, 1.11 to 1.99; p=0.007). Atropine use negatively predicted SHD (AdjOR=0.06, 0.02 to 0.22; p<0.001). Predictors of ROSC ALS paramedic on scene (AdjOR=8.90, 1.11 to 71.41; p=0.04) and successful intubation (AdjOR=3.35, 1.75 to 6.39; p<0.001). Atropine use negatively predicted ROSC (AdjOR=0.27, 0.14 to 0.50; p<0.001).

Conclusions

Presenting prehospital ECG characteristics did not predict SHD or ROSC in OHCA PEA victims and should not be used to guide termination of resuscitation. Location of arrest was a positive predictor for SHD; atropine use was a negative predictor. ALS paramedic on scene and successful intubation were positive predictors of ROSC; atropine use was a negative predictor.

Trial registration number

NCT00394706; post-results.

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