ABSTRACT
Ankylosing spondylitis (AS) presents with renal failure and proteinuria in a minority of cases, usually due to secondary amyloidosis or IgA nephropathy. While focal segmental glomerulosclerosis (FSGS) is less common, it should still be in the differential regardless of the patient's clinical profile.
ABSTRACT
The noninflamed microenvironment in prostate cancer represents a barrier to immunotherapy. Genetic alterations underlying cancer cell-intrinsic oncogenic signaling are increasingly appreciated for their role in shaping the immune landscape. Recently, we identified Pygopus 2 (PYGO2) as the driver oncogene for the amplicon at 1q21.3 in prostate cancer. Here, using transgenic mouse models of metastatic prostate adenocarcinoma, we found that Pygo2 deletion decelerated tumor progression, diminished metastases, and extended survival. Pygo2 loss augmented the activation and infiltration of cytotoxic T lymphocytes (CTLs) and sensitized tumor cells to T cell killing. Mechanistically, Pygo2 orchestrated a p53/Sp1/Kit/Ido1 signaling network to foster a microenvironment hostile to CTLs. Genetic or pharmacological inhibition of Pygo2 enhanced the antitumor efficacy of immunotherapies using immune checkpoint blockade (ICB), adoptive cell transfer, or agents inhibiting myeloid-derived suppressor cells. In human prostate cancer samples, Pygo2 expression was inversely correlated with the infiltration of CD8+ T cells. Analysis of the ICB clinical data showed association between high PYGO2 level and worse outcome. Together, our results highlight a potential path to improve immunotherapy using Pygo2-targeted therapy for advanced prostate cancer.
Subject(s)
Prostatic Neoplasms , T-Lymphocytes, Cytotoxic , Male , Mice , Animals , Humans , Chromatin/metabolism , CD8-Positive T-Lymphocytes , Prostatic Neoplasms/genetics , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Immunotherapy , Mice, Transgenic , Tumor Microenvironment , Intracellular Signaling Peptides and Proteins/geneticsABSTRACT
The International Classification of Diseases (ICD) system includes sub codes to indicate that an individual with epilepsy is treatment resistant. These codes would be a valuable tool to identify individuals for quality improvement and population health, as well as for recruitment into clinical trials. However, the accuracy of these codes is unclear. We performed a single center cross sectional study to understand the accuracy of ICD codes for treatment resistant epilepsy. We identified 344 individuals, roughly half with treatment resistant epilepsy The ICD code had a sensitivity of 90% (147 of 164) and specificity of 86% (155 of 180). The miscoding of children with refractory epilepsy was attributed to the following reasons: 5 patients had epilepsy surgery, 4 had absence epilepsy, 4 patients were seen by different providers, and 1 patient was most recently seen in movement disorders clinic. ICD codes accurately identify children with treatment resistant epilepsy.
ABSTRACT
OBJECTIVE: Status epilepticus is a life-threatening neurological emergency. However, delay in median time to administration of second-line antiseizure medication exists. The aim of this quality improvement initiative was to decrease the average delay before fosphenytoin is administered for pediatric patients with generalized convulsive status epilepticus from 30 min (baseline data collected in 2013) to 15 min (50% reduction) by December 2015 and sustain this for 1 year. METHODS: Our team conducted an analysis of baseline data for patients with continuous generalized convulsive status epilepticus who received fosphenytoin after receiving first-line benzodiazepine treatment. Using quality improvement methodology, areas for improvement were identified and specific interventions developed and implemented. A timeline of 15 min to initiate fosphenytoin administration after failure of first-line treatment was considered reasonable and achievable as a project aim. RESULTS: A total of 199 patients were included in the dataset for the project. The database included patients aged 1 month and older. Ninety-eight percent of patients were between 1 month and 19 years of age. The gender distribution was even, with 54% of patients being White or Caucasian, 30% African American or Black, and 16% classified as "other." From January 2014 through December 2019, the average time before initiating fosphenytoin administration after failure of benzodiazepine therapy, for patients with generalized convulsive status epilepticus, decreased from 30 min (SD = 45.7) to 11.4 min (SD = 8.2, p = .043), thus reducing time to administration by 62%. SIGNIFICANCE: Quality improvement methodology can be successfully applied to decrease administration time between first- and second-line antiseizure medications for status epilepticus.
Subject(s)
Quality Improvement , Status Epilepticus , Anticonvulsants/adverse effects , Benzodiazepines/therapeutic use , Child , Databases, Factual , Humans , Status Epilepticus/chemically inducedABSTRACT
BACKGROUND: Recent genomic profiling has identified a subtype of prostate cancer (PCa) characterized by two key genetic alterations: missense mutation of speckle-type POZ protein (SPOP) and homozygous deletion of chromodomain helicase DNA-binding protein 1 (CHD1). Mutually exclusive with E26 transformation-specific (ETS) rearrangements, this subtype displays high genomic instability. Previous studies indicate that deficient SPOP or CHD1 alone leads to feeble prostate abnormalities and each protein is involved in DNA damage response (DDR). It remains to be determined whether CHD1 and SPOP cooperate to suppress prostate tumorigenesis and DDR. METHODS: Prostate-specific single or double knockout of Spop and Chd1 was generated with the Cre/loxP system in mice. Wild-type or mutant SPOP (F102C, F133V) overexpression and CHD1 knockdown with short hairpin RNA were created in human benign prostatic hyperplasia cell line BPH1. The levels of DNA damage and homologous recombination repair were measured by immunofluorescence staining of γH2AX and RAD51, respectively. RESULTS: Spop/Chd1 double-knockout mice displayed prostatic intraepithelial neoplasia at both young (3 months) and old (12 months) ages and failed to generate prostate adenocarcinoma. Compared with wild-type or single-knockout mice, the double-knockout prostate harbored moderately higher proliferating cells and dramatically augmented the level of γH2AX staining, although androgen receptor-positive cells and apoptotic cells remained at a similar level. In BPH1 cell line, SPOP mutant overexpression and CHD1 silencing synergistically sensitized the cells to DNA damage by camptothecin, an inducer of double-strand breaks. CONCLUSIONS: Our results indicate that SPOP and CHD1 can synergistically promote repair of naturally occurring or chemically induced DNA damages in prostate epithelial cells. Regarding the progression of the SPOP/CHD1 subtype of PCa, other functionally complementary drivers warrant further identification. The clinical implication is that this subtype of PCa may be particularly sensitive to poly(ADP-ribose) polymerase inhibitors or DNA-damaging agents.
Subject(s)
DNA Helicases/genetics , DNA-Binding Proteins/genetics , Nuclear Proteins/genetics , Prostate/physiology , Prostatic Neoplasms/genetics , Repressor Proteins/genetics , Ubiquitin-Protein Ligase Complexes/genetics , Animals , DNA Damage , Epithelial Cells/pathology , Gene Expression , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Mutation , Prostate/pathology , Prostatic Hyperplasia/genetics , Prostatic Hyperplasia/pathology , Prostatic Neoplasms/pathologyABSTRACT
OBJECTIVE: Caring for a child with illness or a child with disability impacts family in various ways. The ability to assess the impact of this care on families is one way to proactively provide the necessary support and resources for impacted families. Accordingly, the goal of the current study was to assess the impact of pediatric epilepsy on individual families in a comprehensive epilepsy clinic using a slightly modified version of the Impact on Families Scale (IFS). METHODS: Families of patients with epilepsy completed the IFS up to three times. The IFS score and the six categories (i.e., total impact, financial impact, general impact, family/social impact, coping, and sibling impact) were assessed using Student's two sample t-test to determine the differences between binary groups and Pearson's correlation to assess the associations with continuous variables. Linear regression modeling was used to develop a model to predict IFS score. RESULTS: Three hundred and forty-one patients completed the scale at one time point, 314 at two time points, and 61 at three time points. The overall impact of epilepsy on families was 109 (95% confidence interval (CI): 106-112) at time point 1, 111 (95% CI: 108-114) at time point 2, and 112 (95% CI: 105-119) at time point 3. There was no statistical difference in IFS score among the three time points. There were no associations with age or gender. Multivariable modeling using stepwise regression indicated that treatment resistance and seizure-free status were associated with IFS score. No interaction effects were identified. CONCLUSIONS: Findings from the current study suggest that the impact of epilepsy is highest for families that have children with active seizures at the time of their clinical visit and for those with children having treatment-resistant epilepsy. Although intuitive, this is the first study, to our knowledge, that has empirically verified these findings.
Subject(s)
Cost of Illness , Epilepsy/psychology , Family/psychology , Hospitals, Pediatric/trends , Adolescent , Child , Child, Preschool , Drug Resistant Epilepsy/diagnosis , Drug Resistant Epilepsy/psychology , Drug Resistant Epilepsy/therapy , Epilepsy/diagnosis , Epilepsy/therapy , Female , Humans , Infant , Infant, Newborn , Male , Retrospective Studies , Young AdultABSTRACT
Currently, the tracking of seizures is highly subjective, dependent on qualitative information provided by the patient and family instead of quantifiable seizure data. Usage of a seizure detection device to potentially detect seizure events in a population of epilepsy patients has been previously done. Therefore, we chose the Fitbit Charge 2 smart watch to determine if it could detect seizure events in patients when compared to continuous electroencephalographic (EEG) monitoring for those admitted to an epilepsy monitoring unit. A total of 40 patients were enrolled in the study that met the criteria between 2015 and 2016. All seizure types were recorded. Twelve patients had a total of 53 epileptic seizures. The patient-aggregated receiver operating characteristic curve had an area under the curve of 0.58 [0.56, 0.60], indicating that the neural network models were generally able to detect seizure events at an above-chance level. However, the overall low specificity implied a false alarm rate that would likely make the model unsuitable in practice. Overall, the use of the Fitbit Charge 2 activity tracker does not appear well suited in its current form to detect epileptic seizures in patients with seizure activity when compared to data recorded from the continuous EEG.
Subject(s)
Epilepsy/complications , Fitness Trackers , Monitoring, Physiologic/methods , Seizures/diagnosis , Seizures/etiology , Adolescent , Adult , Child , Female , Humans , Machine Learning , Male , Reproducibility of Results , Young AdultABSTRACT
Benign familial neonatal epilepsy is a syndrome characterized by recurrent seizures occurring in the neonatal period. Seizures commonly begin at day 3 of life and usually abate by 1 to 4 months of life. Seizures are usually described as tonic with an asymmetric component with associated autonomic features. The authors report a newborn presenting with an unusual electroclinical phenotype. The electroencephalogram demonstrated an unusual pattern of electrical attenuation at the onset of seizures. Identification of these features is important for early recognition of this neonatal syndrome, as well as initiation of proper therapy.