Deregulation of signaling pathways is a hallmark of malignant transformation. Signaling-associated phosphoproteins can be degraded to generate cancer-specific phosphopeptides that are presented by ...major histocompatibility complex (MHC) class I and II molecules and recognized by T cells; however, the contribution of these phosphoprotein-specific T cells to immune surveillance is unclear. We identified 95 phosphopeptides presented on the surface of primary hematological tumors and normal tissues, including 61 that were tumor-specific. Phosphopeptides were more prevalent on more aggressive and malignant samples. CD8(+) T cell lines specific for these phosphopeptides recognized and killed both leukemia cell lines and human leukocyte antigen-matched primary leukemia cells ex vivo. Notably, healthy individuals showed robust CD8(+) T cell responses against many of these phosphopeptides within the circulating memory compartment. This immunity was significantly reduced or absent in some leukemia patients. This reduction correlated with clinical outcome; however, immunity was restored after allogeneic stem cell transplantation. These results suggest that phosphopeptides may be targets of cancer immune surveillance in humans, and point to their importance for development of vaccine-based and T cell adoptive transfer immunotherapies.
OBJECTIVES
To investigate the association between depressive symptoms and several medical morbidities, and their combination, in a large older population.
DESIGN
Cross‐sectional study of baseline ...data from the ASPirin in Reducing Events in the Elderly (ASPREE) trial.
SETTING
Multicentric study conducted in Australia and the United States.
PARTICIPANTS
A total of 19,110 older adults (mean age = 75 years standard deviation = ±4.5).
MEASUREMENTS
Depressive symptoms were measured using the Center for Epidemiological Studies Depression (CES‐D 10) scale. Medical morbidities were defined according to condition‐specific methods. Logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs) to test associations before and after accounting for possible confounders.
RESULTS
Depressive symptoms were significantly associated with obesity (OR = 1.19; 95% CI = 1.07‐1.32), diabetes (OR = 1.22; 95% CI = 1.05‐1.42), gastroesophageal reflux disease (GERD) (OR = 1.41; 95% CI = 1.28‐1.57), metabolic syndrome (OR = 1.16; 95% CI = 1.03‐1.29), osteoarthritis (OR = 1.41; 95% CI = 1.27‐1.57), respiratory conditions (OR = 1.25; 95% CI = 1.10‐1.42), history of cancer (OR = 1.19; 95% CI = 1.05‐1.34), Parkinson’s disease (OR = 2.56; 95% CI = 1.83‐3.56), polypharmacy (OR = 1.60; 95% CI = 1.44‐1.79), and multimorbidity (OR = 1.29; 95% CI = 1.12‐1.49). No significant association was observed between depressive symptoms and hypertension, chronic kidney disease, dyslipidemia, and gout (P > .05). A significant dose‐response relationship was evident between the number of medical comorbidities and the prevalence of depression (OR = 1.18; 95% CI = 1.13‐1.22).
CONCLUSION
Late‐life depressive symptoms are significantly associated with several medical morbidities, and there appears to be a cumulative effect of the number of somatic diseases on the prevalence of depression. These findings augment the evidence for a complex relationship between mental and physical health in an otherwise healthy older population and might guide clinicians toward early recognition of high‐risk individuals. J Am Geriatr Soc 68:1834‐1841, 2020.
Despite unprecedented clinical activity in mantle cell lymphoma (MCL), primary and acquired resistance to ibrutinib is common. The outcomes and ideal management of patients who experience ibrutinib ...failure are unclear. We performed a retrospective cohort study of all patients with MCL who experienced disease progression while receiving ibrutinib across 15 international sites. Medical records were evaluated for clinical characteristics, pathological and radiological data, and therapies used pre- and postibrutinib. A total of 114 subjects met eligibility criteria. The median number of prior therapies was 3 (range, 0-10). The Mantle Cell Lymphoma International Prognostic Index (MIPI) scores at the start of ibrutinib were low, intermediate, and high in 46%, 31%, and 23% of patients, respectively. Of patients with available data prior to ibrutinib and postibrutinib, 34 of 47 and 11 of 12 had a Ki67 >30%. The median time on ibrutinib was 4.7 months (range 0.7-43.6). The median overall survival (OS) following cessation of ibrutinib was 2.9 months (95% confidence interval CI, 1.6-4.9). Of the 104 patients with data available, 73 underwent subsequent treatment an average of 0.3 months after stopping ibrutinib with a median OS of 5.8 months (95% CI, 3.7-10.4). Multivariate Cox regression analysis of MIPI before postibrutinib treatment, and subsequent treatment with bendamustine, cytarabine, or lenalidomide failed to reveal any association with OS. Poor clinical outcomes were noted in the majority of patients with primary or secondary ibrutinib resistance. We could not identify treatments that clearly improved outcomes. Future trials should focus on understanding the mechanisms of ibrutinib resistance and on treatment after ibrutinib.
•Patients with mantle cell lymphoma who progressed during treatment with ibrutinib have a poor outcome.•There are no therapies that appear to be uniquely successful in the postibrutinib setting. The postibrutinib setting is an unmet need.
Bendamustine HCl is a bifunctional mechlorethamine derivative with clinical activity in the treatment of non-Hodgkin's lymphoma. This study evaluated bendamustine plus rituximab in 67 adults with ...relapsed, indolent B-cell or mantle cell lymphoma without documented resistance to prior rituximab.
Patients received rituximab 375 mg/m(2) intravenously on day 1 and bendamustine 90 mg/m(2) intravenously on days 2 and 3 of each 28-day cycle for four to six cycles. An additional dose of rituximab was administered 1 week before the first cycle and 4 weeks after the last cycle. Sixty-six patients (median age, 60 years) received at least one dose of both drugs.
Overall response rate was 92% (41% complete response, 14% unconfirmed complete response, and 38% partial response). Median duration of response was 21 months (95% CI, 18 to 24 months). Median progression-free survival time was 23 months (95% CI, 20 to 26 months). Outcomes were similar for patients with indolent or mantle cell histologies. The combination was generally well tolerated; the primary toxicity was myelosuppression (grade 3 or 4 neutropenia, 36%; grade 3 or 4 thrombocytopenia, 9%).
Bendamustine plus rituximab is an active combination in patients with relapsed indolent and mantle cell lymphoma.
Quantitative diagnosis of glucose-6-phosphate dehydrogenase (G6PD) deficiency is essential for the safe administration of 8-aminoquinoline based radical cure for the treatment of Plasmodium vivax ...infections. Here, we present the PreQuine Platform (IVDS, USA), a quantitative biosensor that uses a dual-analyte assay for the simultaneous measurement of Hemoglobin (Hgb) levels and G6PD enzyme activity within the same sample. The platform relies on a downloadable mobile application. The device requires 10μl of whole blood and works with a reflectance-based meter. Comparing the G6PD measurement normalized by Hgb of 12 samples from the PreQuine Platform with reference measurements methods (spectrophotometry, Pointe Scientific, USA and hemoglobin meter, HemoCue, Sweden) showed a positive and significant agreement with a slope of 1.0091 and an intercept of -0.0379 under laboratory conditions. Next steps will be to conduct field trials in Bangladesh, Cambodia, and the USA to assess diagnostic performance, user friendliness and acceptance.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Comorbid conditions appear to be common among individuals hospitalised with coronavirus disease 2019 (COVID-19) but estimates of prevalence vary and little is known about the prior medication use of ...patients. Here, we describe the characteristics of adults hospitalised with COVID-19 and compare them with influenza patients. We include 34,128 (US: 8362, South Korea: 7341, Spain: 18,425) COVID-19 patients, summarising between 4811 and 11,643 unique aggregate characteristics. COVID-19 patients have been majority male in the US and Spain, but predominantly female in South Korea. Age profiles vary across data sources. Compared to 84,585 individuals hospitalised with influenza in 2014-19, COVID-19 patients have more typically been male, younger, and with fewer comorbidities and lower medication use. While protecting groups vulnerable to influenza is likely a useful starting point in the response to COVID-19, strategies will likely need to be broadened to reflect the particular characteristics of individuals being hospitalised with COVID-19.
Angiographic severity of coronary artery stenosis has historically been the primary guide to revascularization or medical management of coronary artery disease. However, physiologic severity defined ...by coronary pressure and/or flow has resurged into clinical prominence as a potential, fundamental change from anatomically to physiologically guided management. This review addresses clinical coronary physiology—pressure and flow—as clinical tools for treating patients. We clarify the basic concepts that hold true for whatever technology measures coronary physiology directly and reliably, here focusing on positron emission tomography and its interplay with intracoronary measurements.
Angiographic severity of coronary artery stenosis has historically been the primary guide to revascularization or medical management of coronary artery disease. However, physiologic severity defined ...by coronary pressure and/or flow has resurged into clinical prominence as a potential, fundamental change from anatomically to physiologically guided management. This review addresses clinical coronary physiology-pressure and flow-as clinical tools for treating patients. We clarify the basic concepts that hold true for whatever technology measures coronary physiology directly and reliably, here focusing on positron emission tomography and its interplay with intracoronary measurements.
Abstract
Antarctica is one of the most vulnerable regions to climate change on Earth and studying the past and present responses of this polar marine ecosystem to environmental change is a matter of ...urgency. Sedimentary ancient DNA (
sed
aDNA) analysis can provide such insights into past ecosystem-wide changes. Here we present authenticated (through extensive contamination control and
sed
aDNA damage analysis) metagenomic marine eukaryote
sed
aDNA from the Scotia Sea region acquired during IODP Expedition 382. We also provide a marine eukaryote
sed
aDNA record of ~1 Mio. years and diatom and chlorophyte
sed
aDNA dating back to ~540 ka (using taxonomic marker genes SSU, LSU,
psbO
). We find evidence of warm phases being associated with high relative diatom abundance, and a marked transition from diatoms comprising <10% of all eukaryotes prior to ~14.5 ka, to ~50% after this time, i.e., following Meltwater Pulse 1A, alongside a composition change from sea-ice to open-ocean species. Our study demonstrates that
sed
aDNA tools can be expanded to hundreds of thousands of years, opening the pathway to the study of ecosystem-wide marine shifts and paleo-productivity phases throughout multiple glacial-interglacial cycles.
BACKGROUND:Truncating variants in the Titin gene (TTNtvs) are common in individuals with idiopathic dilated cardiomyopathy (DCM). However, a comprehensive genomics-first evaluation of the impact of ...TTNtvs in different clinical contexts, and the evaluation of modifiers such as genetic ancestry, has not been performed.
METHODS:We reviewed whole exome sequence data for >71 000 individuals (61 040 from the Geisinger MyCode Community Health Initiative (2007 to present) and 10 273 from the PennMedicine BioBank (2013 to present) to identify anyone with TTNtvs. We further selected individuals with TTNtvs in exons highly expressed in the heart (proportion spliced in PSI >0.9). Using linked electronic health records, we evaluated associations of TTNtvs with diagnoses and quantitative echocardiographic measures, including subanalyses for individuals with and without DCM diagnoses. We also reviewed data from the Jackson Heart Study to validate specific analyses for individuals of African ancestry.
RESULTS:Identified with a TTNtv in a highly expressed exon (hiPSI) were 1.2% individuals in PennMedicine BioBank and 0.6% at Geisinger. The presence of a hiPSI TTNtv was associated with increased odds of DCM in individuals of European ancestry (odds ratio 95% CI18.7 9.1–39.4 {PennMedicine BioBank} and 10.8 7.0–16.0 {Geisinger}). hiPSI TTNtvs were not associated with DCM in individuals of African ancestry, despite a high DCM prevalence (odds ratio, 1.8 0.2–13.7; P=0.57). Among 244 individuals of European ancestry with DCM in PennMedicine BioBank, hiPSI TTNtv carriers had lower left ventricular ejection fraction (β=–12%, P=3×10), and increased left ventricular diameter (β=0.65 cm, P=9×10). In the Geisinger cohort, hiPSI TTNtv carriers without a cardiomyopathy diagnosis had more atrial fibrillation (odds ratio, 2.4 1.6–3.6) and heart failure (odds ratio, 3.8 2.4–6.0), and lower left ventricular ejection fraction (β=–3.4%, P=1×10).
CONCLUSIONS:Individuals of European ancestry with hiPSI TTNtv have an abnormal cardiac phenotype characterized by lower left ventricular ejection fraction, irrespective of the clinical manifestation of cardiomyopathy. Associations with arrhythmias, including atrial fibrillation, were observed even when controlling for cardiomyopathy diagnosis. In contrast, no association between hiPSI TTNtvs and DCM was discerned among individuals of African ancestry. Given these findings, clinical identification of hiPSI TTNtv carriers may alter clinical management strategies.
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