The Society for Cardiovascular Magnetic Resonance Registry at 150,000.

BACKGROUND: Cardiovascular magnetic resonance (CMR) is increasingly utilized to evaluate expanding cardiovascular conditions. The Society for Cardiovascular Magnetic Resonance (SCMR) Registry is a central repository for real-world clinical data to support cardiovascular research, including those relating to outcomes, quality improvement, and machine learning. The SCMR Registry is built on a regulatory-compliant, cloud-based infrastructure that houses searchable content and Digital Imaging and Communications in Medicine images. The goal of this study is to summarize the status of the SCMR Registry at 150,000 exams. METHODS: The processes for data security, data submission, and research access are outlined. We interrogated the Registry and presented a summary of its contents. RESULTS: Data were compiled from 154,458 CMR scans across 20 United States sites, containing 299,622,066 total images (∼100 terabytes of storage). Across reported values, the human subjects had an average age of 58 years (range 1 month to >90 years old), were 44% (63,070/145,275) female, 72% (69,766/98,008) Caucasian, and had a mortality rate of 8% (9,962/132,979). The most common indication was cardiomyopathy (35,369/131,581, 27%), and most frequently used current procedural terminology code was 75561 (57,195/162,901, 35%). Macrocyclic gadolinium-based contrast agents represented 89% (83,089/93,884) of contrast utilization after 2015. Short-axis cines were performed in 99% (76,859/77,871) of tagged scans, short-axis late gadolinium enhancement (LGE) in 66% (51,591/77,871), and stress perfusion sequences in 30% (23,241/77,871). Mortality data demonstrated increased mortality in patients with left ventricular ejection fraction <35%, the presence of wall motion abnormalities, stress perfusion defects, and infarct LGE, compared to those without these markers. There were 456,678 patient-years of all-cause mortality follow-up, with a median follow-up time of 3.6 years. CONCLUSION: The vision of the SCMR Registry is to promote evidence-based utilization of CMR through a collaborative effort by providing a web mechanism for centers to securely upload de-identified data and images for research, education, and quality control. The Registry quantifies changing practice over time and supports large-scale real-world multicenter observational studies of prognostic utility.

Uveitis and Scleritis as a Risk Factor for Mortality.

PURPOSE: Uveitis and scleritis may be caused by local or systemic infection, or associated with noninfectious systemic inflammatory autoimmune disease. This study explored the all-cause mortality following an individual's first presentation with uveitis/scleritis. METHODS: A cross-sectional study was conducted on all uveitis/scleritis patients diagnosed by uveitis specialists and treated in a single tertiary referral center in New Zealand between 2006 and 2020(15y). Masquerade syndromes including intraocular lymphoma were excluded. Outcome measures: demographics, etiology of uveitis/scleritis, anatomical location and all-cause mortality. RESULTS: 2723 subjects were identified. Median age of onset of uveitis/scleritis was 44.9 years (Range:1.5-99.5 years). 49.6% were female. Median follow-up from diagnosis of uveitis/scleritis was 8.0 years (IQR 4.1-11.6 years) with a total follow-up of 24 443.3 subject-years. The most frequent diagnosis was idiopathic disease (30.9%), HLA-B27-positive uveitis (20.0%), and sarcoidosis (4.7%). Infectious etiologies (24.1%) were most commonly from herpes zoster virus (9.3%) and toxoplasmosis (4.3%). The age-adjusted mortality rate was higher in subjects with idiopathic disease, sarcoidosis, Fuchs' uveitis syndrome, granulomatosis with polyangiitis/ANCA-associated vasculitis, toxoplasmosis, and herpes zoster virus, when compared to HLA-B27-positive uveitis. Hazard of mortality peaked in the first seven years following diagnosis, then subsequently declined. Patients with uveitis/scleritis had a significantly higher rate of mortality compared to the general New Zealand population (IRR 1.656 p = 0.017). CONCLUSION: Infectious etiologies of uveitis/scleritis in this cohort were high when compared to other developed nations, attributable to data from a tertiary referral center treating inpatients. Potential shared inflammatory mechanisms in the eye and other organs can lead to concurrent non-ocular disease requiring systemic treatment, impacting an individual's longevity.

Evaluation of the rapid Idylla IDH1-2 mutation assay in FFPE glioma samples.

IDH1 and IDH2 mutational status is a critical biomarker with diagnostic, prognostic, and treatment implications in glioma. Although IDH1 p.R132H-specific immunohistochemistry is available, it is unable to identify other mutations in IDH1/2. Next-generation sequencing can accurately determine IDH1/2 mutational status but suffers from long turnaround time when urgent treatment planning and initiation is medically necessary. The Idylla assay can detect IDH1/2 mutational status from unstained formalin-fixed paraffin-embedded (FFPE) slides in as little as a few hours. In a clinical validation, we demonstrate clinical accuracy of 97% compared to next-generation sequencing. Sensitivity studies demonstrated a limit of detection of 2.5-5% variant allele frequency, even at DNA inputs below the manufacturer's recommended threshold. Overall, the assay is an effective and accurate method for rapid determination of IDH1/2 mutational status.

Survival of patients with cervical cancer in India - findings from 11 population based cancer registries under National Cancer Registry Programme.

Background: Cancer survival data from Population Based Cancer Registries (PBCR) reflect the average outcome of patients in the population, which is critical for cancer control efforts. Despite decreasing incidence rates, cervical cancer is the second most common female cancer in India, accounting for 10% of all female cancers. The objective of the study is to estimate the five-year survival of patients with cervical cancer diagnosed between 2012 and 2015 from the PBCRs in India. Methods: A single primary incidence of cervical cancer cases of 11 PBCRs (2012-2015) was followed till June 30, 2021 (n = 5591). Active follow-ups were conducted through hospital visits, telephone calls, home or field visits, and public databases. Five-year Observed Survival (OS) and Age Standardised Relative Survival (ASRS) was calculated. OS was measured by age and clinical extent of disease for cervical cancers. Findings: The five-year ASRS (95% CI) of cervical cancer was 51.7% (50.2%-53.3%). Ahmedabad urban (61.5%; 57.4%-65.4%) had a higher survival followed by Thiruvananthapuram (58.8%; 53.1%-64.3%) and Kollam (56.1%; 50.7%-61.3%). Tripura had the lowest overall survival rate (31.6%; 27.2%-36.1%). The five-year OS% for pooled PBCRs was 65.9%, 53.5%, and 18.0% for localised, regional, and distant metastasis, respectively. Interpretation: We observed a wide variation in cervical cancer survival within India. The findings of this study would help the policymakers to identify and address inequities in the health system. We re-emphasise the importance of awareness, early detection, and increase the improvement of the health care system. Funding: The National Cancer Registry Programme is funded through intra-mural funding by Indian Council of Medical Research, Department of Health Research, India, Ministry of Health & Family Welfare.

Psychotropic Medication Use and Polypharmacy Among Children and Adolescents Initiating Intensive Behavioral Therapy for Severe Challenging Behavior.

OBJECTIVE: To evaluate the prevalence, trends, and factors associated with psychotropic medication use and polypharmacy among children and adolescents initiating intensive behavioral therapy for severe challenging behavior over a 10-year period. STUDY DESIGN: In this retrospective observational study, we examined data from caregiver interviews and patient medical records on the number and types of psychotropic medications prescribed to patients initiating intensive behavioral therapy between January 1, 2013, and December 31, 2022. Trends in medication use and polypharmacy across the 10-year period were analyzed using regression analysis, while differences in demographics and clinical factors for patients with use and polypharmacy were analyzed using nonparametric statistical analysis with odds ratios presented for significant factors. RESULTS: Data from all 302 pediatric patients initiating intensive behavioral therapy across the 10-year period were analyzed. Among all patients and all years, 83.8% were taking at least 1 psychotropic medication and 68.2% experienced polypharmacy. There were no changes in the prevalence of use, mean number of medications taken, or polypharmacy across the 10-year period. Patients diagnosed with attention-deficit/hyperactivity disorder or anxiety disorder, as well as those exhibiting self-injurious behavior had higher use of psychotropic medication and polypharmacy and were taking more medications overall. CONCLUSIONS: Psychotropic medication use and polypharmacy were extremely high for children and adolescents with severe challenging behavior, but use and polypharmacy did not change over the 10-year period of data collection. Further research is needed to establish the generality of these findings to other regions of the US.

Neuroprotective potential of pyrazole benzenesulfonamide derivative T1 in targeted intervention against PTZ-induced epilepsy-like condition in in vivo zebrafish model.

Epilepsy is a chronic neurological disease characterized by a persistent susceptibility to seizures. Pharmaco-resistant epilepsies, impacting around 30 % of patients, highlight the urgent need for improved treatments. Neuroinflammation, prevalent in epileptogenic brain regions, is a key player in epilepsy, prompting the search for new mechanistic therapies. Hence, in this study, we explored the anti-inflammatory potential of pyrazole benzenesulfonamide derivative (T1) against pentylenetetrazole (PTZ) induced epilepsy-like conditions in in-vivo zebrafish model. The results from the survival assay showed 79.97 ± 6.65 % at 150 µM of T1 compared to PTZ-group. The results from reactive oxygen species (ROS), apoptosis and histology analysis showed that T1 significantly reduces cellular damage due to oxidative stress in PTZ-exposed zebrafish. The gene expression analysis and neutral red assay results demonstrated a notable reduction in the inflammatory response in zebrafish pre-treated with T1. Subsequently, the open field test unveiled the anti-convulsant activity of T1, particularly at a concentration of 150 µM. Moreover, both RT-PCR and immunohistochemistry findings indicated a concentration-dependent potential of T1, which inhibited COX-2 in zebrafish exposed to PTZ. In summary, T1 protected zebrafish against PTZ-induced neuronal damage, and behavioural changes by mitigating the inflammatory response through the inhibition of COX-2.

Neuronal IL-17 controls Caenorhabditis elegans developmental diapause through CEP-1/p53.

During metazoan development, how cell division and metabolic programs are coordinated with nutrient availability remains unclear. Here, we show that nutrient availability signaled by the neuronal cytokine, ILC-17.1, switches Caenorhabditis elegans development between reproductive growth and dormancy by controlling the activity of the tumor suppressor p53 ortholog, CEP-1. Specifically, upon food availability, ILC-17.1 signaling by amphid neurons promotes glucose utilization and suppresses CEP-1/p53 to allow growth. In the absence of ILC-17.1, CEP-1/p53 is activated, up-regulates cell-cycle inhibitors, decreases phosphofructokinase and cytochrome C expression, and causes larvae to arrest as stress-resistant, quiescent dauers. We propose a model whereby ILC-17.1 signaling links nutrient availability and energy metabolism to cell cycle progression through CEP-1/p53. These studies describe ancestral functions of IL-17 s and the p53 family of proteins and are relevant to our understanding of neuroimmune mechanisms in cancer. They also reveal a DNA damage-independent function of CEP-1/p53 in invertebrate development and support the existence of a previously undescribed C. elegans dauer pathway.

Insights into the diagnosis and management of sarcoid uveitis: A review.

Sarcoidosis is a leading cause of non-infectious uveitis that commonly affects middle-aged individuals and has a female preponderance. The disease demonstrates age, sex and ethnic differences in clinical manifestations. A diagnosis of sarcoidosis is made based on a compatible clinical presentation, supporting investigations and histologic evidence of non-caseating granulomas, although biopsy is not always possible. Multimodal imaging with widefield fundus photography, optical coherence tomography and angiography can help in the diagnosis of sarcoid uveitis and in the monitoring of treatment response. Corticosteroid remains the mainstay of treatment; chronic inflammation requires steroid-sparing immunosuppression. Features on multimodal imaging such as vascular leakage may provide prognostic indicators of outcome. Female gender, prolonged and severe uveitis, and posterior involving uveitis are associated with poorer visual outcomes.

Clinical and Anatomical Variation During Assessment of Maximum Glottic Angle.

INTRODUCTION: Quantitative measurement and analysis of glottic abduction is used to assess laryngeal function and success of interventions; however, the consistency of measurement over time has not been established. This study assesses the consistency of glottic abduction measurements across visits in healthy patients and anatomic factors impacting these measurements. METHODS: Review of patients with two sequential flexible stroboscopic exams over seven months from 2019-2022. Images of maximal glottic abduction were captured and uploaded into and measured with ImageJ. Cadaver heads were used to assess the impact of visualization angles on glottic measurements with a monofilament inserted into the supraglottis of each cadaver as a point of reference. Comparisons were done with a paired T-test, T-test, or Mann-Whitney U test as appropriate. RESULTS: Fifty-nine patients and twenty-six cadaveric exams were included. Absolute change in maximum glottic abduction angle (MGAA) was 6.90° (95% CI [5.36°, 8.42°]; p < 0.05). There were no significant differences in change in MGAA by gender or age. Twenty percent of patients had a change of at least 25% in their MGAA between visits. Absolute differences in glottic angle between nasal side for cadaveric measurements was 4.77 ± 4.59° (p < 0.005)-2.22° less than the change in MGAA seen over time (p = 0.185). CONCLUSION: Maximal glottic abduction angles varied significantly between visits. Factors considered to be contributing to the differences include different viewing windows between examinations due to the position and angulation of the laryngoscope and changes in patient positioning, intra- and inter-rater variations in measurement, and patient effort. LEVEL OF EVIDENCE: N/a Laryngoscope, 134:2793-2798, 2024.

Acute posterior multifocal placoid pigment epitheliopathy: clinical presentation and risk of stroke and transient ischaemic attack.

BACKGROUND/AIMS: Acute posterior multifocal placoid pigment epitheliopathy is a rare but important disease that can be associated with life-threatening complications due to cerebral vasculitis. The primary objective was to determine the incidence of neurological complications and risk factors for stroke and transient ischaemic attack (TIA) associated with acute posterior multifocal placoid pigment epitheliopathy. Secondary objectives included the clinical presentation, visual outcomes and recurrence rates. METHODS: This was a multicentre retrospective case series including 111 eyes from 60 subjects presenting from January 2009 to June 2020. RESULTS: Median age at presentation was 29 years (IQR 24.7-35.1) and 36 subjects (60.0%) were male. 20 subjects (33.3%) reported a viral prodrome. Stroke and TIA were observed in seven subjects (11.7%). Older age was the only significant risk factor for stroke/TIA (p=0.042). Vision loss occurred in seven eyes, with four eyes (3.6%) having final visual acuity 6/15-6/60 and three eyes (2.7%) having visual acuity of 6/60 or worse. Recurrence occurred in 10 subjects (16.7%). CONCLUSIONS: The presence of headache cannot reliably predict those at risk of stroke/TIA. Individuals presenting with acute posterior multifocal pigment epitheliopathy should therefore undergo a clinical neurological review and work-up for cerebral vasculitis as deemed appropriate by the treating ophthalmologist and collaborating neurologist.

Vaccine Breakthrough Infections Among Healthcare Workers in a COVID-19-Designated Tertiary Care Government Hospital in Sikkim.

Introduction Since the emergence of the coronavirus disease 2019 (COVID-19) virus at the beginning of 2020, the world has gone through various waves of pandemics. The health care workers (HCWs) or the COVID warriors as they were termed were the first line of defense against the virus. They were armed with personal protective equipment and prophylactic doses of the COVID-19 vaccine. Despite these precautions, some of the HCWs still contracted the disease and a few others succumbed to it. The objective of this study was to estimate the prevalence of COVID-19 infections and vaccine breakthrough infections (BTIs) in HCWs after receiving the COVID-19 vaccine during the second wave of the pandemic. Methods This was a cross-sectional, hospital-based study conducted over a period of four months from September 2021 to December 2021 on HCWs aged 18 years and above working at the COVID-19-designated tertiary care government hospital in Sikkim. A structured coded questionnaire with no patient identifiers was used to gather details on demographics, vaccination history, breakthrough infection, and other social details. HCWs who had received at least one dose of the COVID-19 vaccine at the time of initiation of the study and were >18 years of age were included in this study. Results A total of 678 HCWs were screened, out of which 229 (33%) participants tested positive for COVID-19 and the rest of the participants (455; 67%) tested negative. COVID-19 infections and vaccine BTIs (COVID-19 infection >14 days after the second vaccination) were recorded and 137 (20%) respondents had a post-vaccination COVID-19 infection out of which 115 (18.5%) were BTI. The majority of the participants were females and of the age group of 26-35 years. The correlation of COVID-19 infections with the dose gap between vaccination, gender, age, profession, department, area posted during COVID duty, cycles of duty performed, hospitalization due to infection, influenza vaccination, and comorbidity was analyzed. Conclusion COVID-19 vaccines are disease-modifying and they decrease the severity of BTIs in HCWs. Pandemics and outbreaks cannot be predicted; therefore, it becomes very important to have healthy frontline workers who are constantly exposed to infectious agents. Monitoring of health and surveillance of infectious diseases among the HCWs should be encouraged.

The spectrum of paediatric uveitis in New Zealand.

AIMS: To describe the aetiology, complications, treatment and outcomes of paediatric uveitis. METHODS: This was a retrospective chart review including all paediatric participants presenting with uveitis to a tertiary referral hospital in Auckland, New Zealand between January 1997 and March 2020. RESULTS: Two hundred and twenty-four eyes of 143 participants were included. One hundred and three (46.0%) eyes were found to have uveitis without the child reporting any symptoms. Non-infectious uveitis occurred in 97 (67.8%) participants and infectious aetiology occurred in 46 (32.2%) participants. One hundred and twenty-six (56.3%) eyes developed complications by final follow-up, including ocular hypertension (60 eyes, 26.8%), cataract (55 eyes, 24.6%) and glaucoma (21 eyes, 9.4%). Conventional disease modifying anti-rheumatic drugs (DMARDs) were required in 58 (59.8%) participants, and biologic disease modifying anti-rheumatic drugs in 31 (32.0%) participants with non-infectious uveitis. Participants who were younger at presentation were more likely to require a DMARD (OR 0.896 p=0.032). Vision loss of 6/15 or worse occurred in 38 (17.0%) eyes. CONCLUSIONS: Infections are an important cause of uveitis in this age group. Asymptomatic presentation and complications commonly occur. A large proportion of children with non-infectious uveitis will require steroid sparing immunosuppression.

In-silico studies of 2-aminothiazole derivatives as anticancer agents by QSAR, molecular docking, MD simulation and MM-GBSA approaches.

Targeting Hec1/Nek2 is considered as crucial target for cancer treatment due to its significant role in cell proliferation. In pursuit of this, a series of twenty-five 2-aminothiazoles derivatives, along with their Hec1/Nek2 inhibitory activities were subjected to QSAR studies utilizing QSARINS software. The significant three descriptor QSAR model was generated, showing noteworthy statistical parameters: a correlation coefficient of cross validation leave one out (Q2LOO) = 0.7965, coefficient of determination (R2) = 0.8436, (R2ext) = 0.6308, cross validation leave many out (Q2LMO) = 0.7656, Concordance Correlation Coefficient (CCCCV = 0.8875), CCCtr = 0.9151, and CCCext = 0.0.7241. The descriptors integral to generated QSAR model include Moreau-Broto autocorrelation, which represents the spatial autocorrelation of a property along the molecular graph's topological structure (ATSC1i), Moran autocorrelation at lag 8, which is weighted by charges (MATS8c) and RPSA representing the total molecular surface area. It was noted that these descriptors significantly influence Hec1/Nek2 inhibitory activity of 2-aminothiazoles derivatives. New lead molecules were designed and predicted for their Hec1/Nek2 inhibitory activity based on the developed three descriptor model. Further, the ADMET and Molecular docking studies were carried out for these designed molecules. The three molecules were selected based on their docking score and further subjected for MD simulation studies. Post-MD MM-GBSA analysis were also performed to predicted the free binding energies of molecules. The study helped us to understand the key interactions between 2-aminothiazoles derivatives and Hec1/Nek2 protein that may be necessary to develop new lead molecules against cancer.Communicated by Ramaswamy H. Sarma.

Long term outcome and prognostic indicators in Posner Schlossman syndrome.

BACKGROUND: Posner Schlossman syndrome is a well-defined uveitis entity that is characterised by relapsing remitting unilateral anterior uveitis with markedly raised intraocular pressure. The aim of this study was to determine the risk factors for progression in patients with Posner Schlossman syndrome. METHODS: Ninety-eight patients were enrolled in a retrospective case series. Progression was defined as a composite endpoint of any of development of permanent glaucoma (in patients with no evidence of glaucomatous loss on presentation), corneal failure, or chronic inflammation. Relapse was defined as a resolving episode of inflammation not meeting the criteria for progression. RESULTS: Seventy seven percent of patients relapsed on average each 2.2 years. Forty percent of patients progressed. On univariate analysis, increased age at enrolment, immunocompromise at enrolment, the presence of glaucomatous optic neuropathy at enrolment, the performance of an anterior chamber tap and a positive anterior chamber tap were all associated with increased risk of progression. On multivariate analysis, age at enrolment, immunocompromise at enrolment, the performance of an anterior chamber tap, and the presence of glaucomatous optic neuropathy at enrolment were independently associated with increased risk of disease progression. CONCLUSIONS: Posner Schlossman syndrome is not a benign uveitis entity and risk of both relapse and progression are high. Older patients, immunocompromised patients, patients with glaucomatous optic neuropathy at enrolment and those with a positive anterior chamber tap are all at increased risk of progression.

Primary ductal adenocarcinoma of the lacrimal gland with sarcomatoid differentiation: case report and genomic analysis.

We describe a case of primary ductal adenocarcinoma of the lacrimal gland with novel histopathological characteristics corresponding to a biphasic growth course and provide a comprehensive genomic profile of this malignancy. A 39-year-old male with a history of slowly progressive unilateral proptosis and hypoglobus presented after 1 month of hyperacute exacerbation. Orbital imaging revealed a superior mass with osseous erosion. The patient underwent orbital exploration and excisional biopsy via lateral orbitotomy. Histopathology demonstrated high-grade adenocarcinoma with a well-differentiated glandular component alongside a poorly differentiated sarcomatoid region. The glandular section was immunopositive for Her-2, CK7, GATA3, and androgen receptor. Tumor recurrence necessitated en-bloc exenteration with dural resection alongside adjuvant radiotherapy and chemotherapy. This represents the first report of sarcomatoid differentiation in primary ductal adenocarcinoma of the lacrimal gland, which may incite hyperacute progression. Conversely, GATA3 immunopositivity may correlate with indolent growth. Genomic variants such as SEMA3C represent potential therapeutic targets for this condition.

Evaluation of a Zoonotic Orthopoxvirus PCR Assay for the Detection of Mpox Virus Infection.

An epidemic caused by an outbreak of mpox (formerly monkeypox) in May 2022 rapidly spread internationally, requiring an urgent response from the clinical diagnostics community. A detailed description of the clinical validation and implementation of a laboratory-developed real-time PCR test for detecting nonvariola Orthopoxvirus-specific DNA based on the newly designed RealStar Zoonotic Orthopoxvirus assay is presented. The validation was performed using an accuracy panel (n = 97) comprising skin lesion swabs in universal transport media and from mpox virus genomic DNA spiked into pooled mpox virus-negative remnant universal transport media of lesion specimens submitted for routine clinical testing in the NewYork-Presbyterian Hospital clinical laboratory system. Accuracy testing demonstrated excellent assay agreement between expected and observed results and comparable diagnostic performance to three different reference tests. Analytical sensitivity with 95% detection probability was 126 copies/mL, and analytical specificity, clinical sensitivity, and clinical specificity were 100%. In summary, the RealStar Zoonotic Orthopoxvirus assay provides a sensitive and reliable method for routine diagnosis of mpox infections.

Juvenile idiopathic arthritis and its associated uveitis.

INTRODUCTION: Juvenile idiopathic arthritis is the most common chronic rheumatologic disease in children. Uveitis is the most common extra-articular manifestation of JIA, and it can be a sight-threatening condition. AREAS COVERED: In this review article, we discussed epidemiology, risk factors, clinical presentation, supportive laboratory tests, treatment options, and complications of Juvenile idiopathic arthritis and Juvenile idiopathic arthritis associated uveitis. We covered conventional immunomodulatory therapy and biologic response modifiers agents for different types of Juvenile idiopathic arthritis and their associated uveitis. Finally, we discussed the course of disease, functional outcome, and the quality of life of Juvenile idiopathic arthritis and Juvenile idiopathic arthritis-associated uveitis. EXPERT OPINION: Although clinical outcomes of Juvenile idiopathic arthritis and its associated uveitis have been improved over the past three decades by biologic response modifier agents, a significant proportion of patients require active treatment into adult life therefore screening and monitoring of these patients is required during the patient's entire life. The limited number of food and drug administration approved biologic response modifier agents for the treatment of Juvenile idiopathic arthritis associated uveitis justify more randomized clinical trials with new medications in this field.

FGFR2 mutations promote endometrial cancer progression through dual engagement of EGFR and Notch signalling pathways.

BACKGROUND: Mutations in the receptor tyrosine kinase gene fibroblast growth factor receptor 2 (FGFR2) occur at a high frequency in endometrial cancer (EC) and have been linked to advanced and recurrent disease. However, little is known about how these mutations drive carcinogenesis. METHODS: Differential transcriptomic analysis and two-step quantitative real-time PCR (qRT-PCR) assays were applied to identify genes differentially expressed in two cohorts of EC patients carrying mutations in the FGFR2 gene as well as in EC cells harbouring mutations in the FGFR2. Candidate genes and target signalling pathways were investigated by qRT-PCR assays, immunohistochemistry and bioinformatics analysis. The functional roles of differently regulated genes were analysed using in vitro and in vivo experiments, including 3D-orthotypic co-culture systems, cell proliferation and migration protocols, as well as colony and focus formation assays together with murine xenograft tumour models. The molecular mechanisms were examined using CRISPR/Cas9-based loss-of-function and pharmacological approaches as well as luciferase reporter techniques, cell-based ectodomain shedding assays and bioinformatics analysis. RESULTS: We show that common FGFR2 mutations significantly enhance the sensitivity to FGF7-mediated activation of a disintegrin and metalloprotease (ADAM)17 and subsequent transactivation of the epidermal growth factor receptor (EGFR). We further show that FGFR2 mutants trigger the activation of ADAM10-mediated Notch signalling in an ADAM17-dependent manner, highlighting for the first time an intimate cooperation between EGFR and Notch pathways in EC. Differential transcriptomic analysis in EC cells in a cohort of patients carrying mutations in the FGFR2 gene identified a strong association between FGFR2 mutations and increased expression of members of the Notch pathway and ErbB receptor family. Notably, FGFR2 mutants are not constitutively active but require FGF7 stimulation to reprogram Notch and EGFR pathway components, resulting in ADAM17-dependent oncogenic growth. CONCLUSIONS: These findings highlight a pivotal role of ADAM17 in the pathogenesis of EC and provide a compelling rationale for targeting ADAM17 protease activity in FGFR2-driven cancers.

Functional Impairment in Pediatric Cancer Survivorship.

Care for pediatric cancer survivors must include scheduled, thorough evaluations of potential chronic and late effects resulting from multidimensional cancer treatments. Assessment of functional independence with activities and participation is critical in assuring that survivors can optimally access their environments and pursue educational, occupational, and leisure activities appropriate to their interests and capabilities. Owing to their expertise in both rehabilitation and habilitation, pediatric physiatrists are of great benefit in the care of survivors of pediatric cancer.

DNA demethylation fine-tunes IL-2 production during thymic regulatory T cell differentiation.

Regulatory T (T reg) cells developing in the thymus are essential to maintain tolerance and prevent fatal autoimmunity in mice and humans. Expression of the T reg lineage-defining transcription factor FoxP3 is critically dependent upon T cell receptor (TCR) and interleukin-2 (IL-2) signaling. Here, we report that ten-eleven translocation (Tet) enzymes, which are DNA demethylases, are required early during double-positive (DP) thymic T cell differentiation and prior to the upregulation of FoxP3 in CD4 single-positive (SP) thymocytes, to promote Treg differentiation. We show that Tet3 selectively controls the development of CD25- FoxP3lo CD4SP Treg cell precursors in the thymus and is critical for TCR-dependent IL-2 production, which drive chromatin remodeling at the FoxP3 locus as well as other Treg-effector gene loci in an autocrine/paracrine manner. Together, our results demonstrate a novel role for DNA demethylation in regulating the TCR response and promoting Treg cell differentiation. These findings highlight a novel epigenetic pathway to promote the generation of endogenous Treg cells for mitigation of autoimmune responses.