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"Lisa D. Jones"
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Mutant IDH is sufficient to initiate enchondromatosis in mice
Significance Current genomic and biochemical analysis revealed mutations in isocitrate dehydrogenase ( IDH ) genes associated with several neoplasms and a novel enzymatic activity of IDH mutations to catalyze α-ketoglutarate to d -2-hydroxyglutarate, contributing to tumorigenesis. We identified a broad range of IDH1 mutations, including a previously unidentified IDH1 -R132Q mutation, in cartilage tumors. Cartilage-specific Col2a1-Cre/ERT2;Idh1-R132 mutant knock-in mice developed multiple enchondroma-like lesions. These data show that mutant Idh in growth-plate cells causes persistence of chondrocytes, giving rise to enchondromas adjacent to the growth cartilage in bone.
Enchondromas are benign cartilage tumors and precursors to malignant chondrosarcomas. Somatic mutations in the isocitrate dehydrogenase genes ( IDH1 and IDH2 ) are present in the majority of these tumor types. How these mutations cause enchondromas is unclear. Here, we identified the spectrum of IDH mutations in human enchondromas and chondrosarcomas and studied their effects in mice. A broad range of mutations was identified, including the previously unreported IDH1 -R132Q mutation. These mutations harbored enzymatic activity to catalyze α-ketoglutarate to d -2-hydroxyglutarate ( d -2HG). Mice expressing Idh1 -R132Q in one allele in cells expressing type 2 collagen showed a disordered growth plate, with persistence of type X-expressing chondrocytes. Chondrocyte cell cultures from these animals or controls showed that there was an increase in proliferation and expression of genes characteristic of hypertrophic chondrocytes with expression of Idh1 -R132Q or 2HG treatment. Col2a1-Cre; Idh1 -R132Q mutant knock-in mice (mutant allele expressed in chondrocytes) did not survive after the neonatal stage. Col2a1-Cre/ERT2;Idh1-R132 mutant conditional knock-in mice, in which Cre was induced by tamoxifen after weaning, developed multiple enchondroma-like lesions. Taken together, these data show that mutant IDH or d -2HG causes persistence of chondrocytes, giving rise to rests of growth-plate cells that persist in the bone as enchondromas.
Journal Article
E3 ubiquitin ligase Mule targets β-catenin under conditions of hyperactive Wnt signaling
Wnt signaling, named after the secreted proteins that bind to cell surface receptors to activate the pathway, plays critical roles both in embryonic development and the maintenance of homeostasis in many adult tissues. Two particularly important cellular programs orchestrated by Wnt signaling are proliferation and stem cell self-renewal. Constitutive activation of the Wnt pathway resulting from mutation or improper modulation of pathway components contributes to cancer development in various tissues. Colon cancers frequently bear inactivating mutations of the adenomatous polyposis coli (APC) gene, whose product is an important component of the destruction complex that regulates β-catenin levels. Stabilization and nuclear localization of β-catenin result in the expression of a panel of Wnt target genes. We previously showed that Mule/Huwe1/Arf-BP1 (Mule) controls murine intestinal stem and progenitor cell proliferation by modulating the Wnt pathway via c-Myc. Here we extend our investigation of Mule’s influence on oncogenesis by showing that Mule interacts directly with β-catenin and targets it for degradation under conditions of hyperactive Wnt signaling. Our findings suggest that Mule uses various mechanisms to fine-tune the Wnt pathway and provides multiple safeguards against tumorigenesis.
Journal Article
E3 ubiquitin ligase Mule targets Beta-catenin under conditions of hyperactive Wnt signaling
Wnt signaling, named after the secreted proteins that bind to cell surface receptors to activate the pathway, plays critical roles both in embryonic development and the maintenance of homeostasis in many adult tissues. Two particularly important cellular programs orchestrated by Wnt signaling are proliferation and stem cell self-renewal. Constitutive activation of the Wnt pathway resulting from mutation or improper modulation of pathway components contributes to cancer development in various tissues. Colon cancers frequently bear inactivating mutations of the adenomatous polyposis coli (APC) gene, whose product is an important component of the destruction complex that regulates β-catenin levels. Stabilization and nuclear localization of β-catenin result in the expression of a panel of Wnt target genes. We previously showed that Mule/Huwe1/Arf-BP1 (Mule) controls murine intestinal stem and progenitor cell proliferation by modulating the Wnt pathway via c-Myc. Here we extend our investigation of Mule's influence on oncogenesis by showing that Mule interacts directly with β-catenin and targets it for degradation under conditions of hyperactive Wnt signaling. Our findings suggest that Mule uses various mechanisms to fine-tune the Wnt pathway and provides multiple safeguards against tumorigenesis.
Journal Article
Clinician Nudge to Gynecologic Oncology Referral at Suspected Ovarian Cancer Diagnosis: A Pilot Study
Patients with ovarian cancer live longer when treated by a gynecologic oncologist, a surgeon whose focus is gynecologic tumors. Yet one-third of patients with ovarian cancer are never seen by a gynecologic oncologist. In this pilot study, we identified clinicians whose patients had imaging concerning for ovarian cancer. We sent these clinicians a message recommending referral to gynecologic oncology with a pended referral order, also known as a clinician nudge. We found that a clinician nudge to gynecologic oncology referral increased referral rate of suspected ovarian cancer to 75%. Clinicians indicated that the nudge was acceptable, and 30% changed their referral behavior after the nudge. More patients had surgery with gynecologic oncology after the nudge than similar patients not in the study. One in four patients in the pilot were diagnosed with cancer, all early-stage disease. A clinician nudge makes it easy and straightforward to clinicians to refer patients to gynecologic oncology. A nudge may improve early detection of ovarian cancer, and a larger study is warranted.
Journal Article
Managing sepsis: Electronic recognition, rapid response teams, and standardized care save lives
Sepsis can lead to poor outcomes when treatment is delayed or inadequate. The purpose of this study was to evaluate outcomes after initiation of a hospital-wide sepsis alert program.
Retrospective review of patients ≥18years treated for sepsis.
There were 3917 sepsis admissions: 1929 admissions before, and 1988 in the after phase. Mean age (57.3 vs. 57.1, p=0.94) and Charlson Comorbidity Scores (2.52 vs. 2.47, p=0.35) were similar between groups. Multivariable analyses identified significant reductions in the after phase for odds of death (OR 0.62, 95% CI 0.39–0.99, p=0.046), mean intensive care unit LOS (2.12days before, 95%CI 1.97, 2.34; 1.95days after, 95%CI 1.75, 2.06; p<0.001), mean overall hospital LOS (11.7days before, 95% CI 10.9, 12.7days; 9.9days after, 95% CI 9.3, 10.6days, p<0.001), odds of mechanical ventilation use (OR 0.62, 95% CI 0.39, 0.99, p=0.007), and total charges with a savings of $7159 per sepsis admission (p=0.036). There was no reduction in vasopressor use (OR 0.89, 95% CI 0.75, 0.1.06, p=0.18).
A hospital-wide program utilizing electronic recognition and RRT intervention resulted in improved outcomes in patients with sepsis.
•EHR-based, sepsis-recognition tool provided hourly, hospital-wide sepsis screening.•Adjusted MEWS-SRS score was tailored to screen for sepsis at our institution.•Nurse-led Rapid Response Team was instrumental in sepsis care delivery on the wards.•Hospital-wide sepsis alert order set was based on a simplified 3h bundle.•Associated reductions in mortality, length of stay, and mechanical ventilation use.
Journal Article
MutantIDHis sufficient to initiate enchondromatosis in mice
Enchondromas are benign cartilage tumors and precursors to malignant chondrosarcomas. Somatic mutations in the isocitrate dehydrogenase genes (IDH1andIDH2) are present in the majority of these tumor types. How these mutations cause enchondromas is unclear. Here, we identified the spectrum of IDH mutations in human enchondromas and chondrosarcomas and studied their effects in mice. A broad range of mutations was identified, including the previously unreportedIDH1-R132Q mutation. These mutations harbored enzymatic activity to catalyze α-ketoglutarate to D-2-hydroxyglutarate (D-2HG). Mice expressingIdh1-R132Q in one allele in cells expressing type 2 collagen showed a disordered growth plate, with persistence of type X-expressing chondrocytes. Chondrocyte cell cultures from these animals or controls showed that there was an increase in proliferation and expression of genes characteristic of hypertrophic chondrocytes with expression ofIdh1-R132Q or 2HG treatment. Col2a1-Cre;Idh1-R132Q mutant knock-in mice (mutant allele expressed in chondrocytes) did not survive after the neonatal stage. Col2a1-Cre/ERT2;Idh1-R132 mutant conditional knock-in mice, in which Cre was induced by tamoxifen after weaning, developed multiple enchondroma-like lesions. Taken together, these data show that mutant IDH or D-2HG causes persistence of chondrocytes, giving rise to rests of growth-plate cells that persist in the bone as enchondromas.
Journal Article
A Large-Scale Study of Anxiety and Depression in People with Multiple Sclerosis: A Survey via the Web Portal of the UK MS Register
Studies have found that people with Multiple Sclerosis experience relatively high rates of anxiety and depression. Although methodologically robust, many of these studies had access to only modest sample sizes (N<200). The aims of this study were to use responses gained via the web portal of the UK MS Register (N>4000) to: describe the depression and anxiety profiles of people with MS; to determine if anxiety and depression are related to age or disease duration; and to assess whether the levels of anxiety and depression differ between genders and types of MS.
From its launch in May 2011 to the end of December 2011, 7786 adults with MS enrolled to take part in the UK MS Register via the web portal. The responses to the Hospital Anxiety and Depression Scale (HADS) were collated with basic demographic and descriptive MS data provided at registration and the resulting dataset was analysed in SPSS (v.16).
The mean HADS score among the 4178 respondents was 15.7 (SE 0.117, SD 7.55) with a median of 15.0 (IQR 11). Anxiety and depression rates were notably high, with over half (54.1%) scoring ≥ 8 for anxiety and 46.9% scoring ≥ 8 for depression. Women with relapsing-remitting MS were more anxious than men with this type (p<0.001), and than women with other types of MS (p = 0.017). Within each gender, men and women with secondary progressive MS were more depressed than men or women with other types of MS (p<0.001, p<0.001).
This largest known study of its kind has shown that anxiety and depression are highly prevalent in people with MS, indicating that their mental health needs could be better addressed. These findings support service planning and further research to provide the best care for people with MS to help alleviate these debilitating conditions.
Journal Article
Adaptation and evaluation of a digital dialectical behaviour therapy for youth at clinical high risk for psychosis: A protocol for a feasibility randomized controlled trial
Youth at clinical high risk (CHR) for psychosis often experience emotional dysregulation, psychiatric symptoms, substance use, suicidality, and functional impairment. Dialectical behaviour therapy (DBT) is an evidence-based intervention that improves emotion regulation, clinical outcomes, and functioning across psychiatric populations. Digital adaptations (d-DBT) may enhance accessibility and engagement for CHR youth, but acceptability and potential benefits in this group are unknown.
To adapt d-DBT for CHR youth and evaluate the acceptability of delivering it to this population, as well as the feasibility of a larger-scale clinical trial.
This mixed-methods clinical trial has two phases. In Phase 1, d-DBT will be adapted for CHR youth in collaboration with a lived-experience youth advisory group. In Phase 2, an assessor-masked randomized controlled trial will compare d-DBT (n = 30) with treatment as usual (n = 30). The intervention consists of eight weekly modules, with primary outcomes assessing acceptability, usability, and trial feasibility. Secondary outcomes include changes in emotional dysregulation, psychiatric symptoms, substance use, suicidality, and functioning.
We anticipate that d-DBT will be acceptable to CHR youth and that conducting a larger trial will be feasible. Preliminary findings may demonstrate improvements in emotion regulation, psychiatric symptoms, suicidality, and functioning. Results will guide further refinement of the intervention and inform the design of a confirmatory clinical trial.
ClinicalTrials.gov #NCT06928935.
Journal Article
How People with Multiple Sclerosis Rate Their Quality of Life: An EQ-5D Survey via the UK MS Register
The EQ-5D is a widely-used, standardised, quality of life measure producing health profiles, indices and states. The aims of this study were to assess the role of various factors in how people with Multiple Sclerosis rate their quality of life, based on responses to the EQ-5D received via the web portal of the UK MS Register.
The 4516 responses to the EQ-5D (between May 2011 and April 2012) were collated with basic demographic and descriptive MS data and the resulting dataset was analysed in SPSS (v.20).
The mean health state for people with MS was 59.73 (SD 22.4, median 61), compared to the UK population mean of 82.48 (which is approximately 1SD above the cohort mean). The characteristics of respondents with high health states (at or above +1SD) were: better health profiles (most predictive dimension: Usual Activities), higher health indices, younger age, shorter durations of MS, female gender, relapsing-remitting MS, higher educational attainment and being in paid employment (all p-values<0.001). Conversely, the characteristics of respondents with low health states (at or below -1SD) were: poorer health profiles (most predictive dimension: Mobility), lower health indices, older age, longer durations of MS, male gender, progressive MS, lower educational attainment and having an employment status of sick/disabled (p = 0.0014 for age, all other p-values<0.001). Particular living arrangements were not associated with either the high or low health status groups.
This large-scale study has enabled in-depth analyses on how people with MS rate their quality of life, and it provides new knowledge on the various factors that contribute to their self-assessed health status. These findings demonstrate the impact of MS on quality of life, and they can be used to inform care provision and further research, to work towards enhancing the quality of life of people with MS.
Journal Article