CaMK4 Gene Deletion Induces Hypertension Santulli, Gaetano; Cipolletta, Ersilia; Sorriento, Daniela ...
Journal of the American Heart Association,
August 2012, Letnik:
1, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Background
The expression of calcium/calmodulin‐dependent kinase IV (CaMKIV) was hitherto thought to be confined to the nervous system. However, a recent genome‐wide analysis indicated an association ...between hypertension and a single‐nucleotide polymorphism (rs10491334) of the human CaMKIV gene (CaMK4), which suggests a role for this kinase in the regulation of vascular tone.
Methods and Results
To directly assess the role of CaMKIV in hypertension, we characterized the cardiovascular phenotype of CaMK4−/− mice. They displayed a typical hypertensive phenotype, including high blood pressure levels, cardiac hypertrophy, vascular and kidney damage, and reduced tolerance to chronic ischemia and myocardial infarction compared with wild‐type littermates. Interestingly, in vitro experiments showed the ability of this kinase to activate endothelial nitric oxide synthase. Eventually, in a population study, we found that the rs10491334 variant associates with a reduction in the expression levels of CaMKIV in lymphocytes from hypertensive patients.
Conclusions
Taken together, our results provide evidence that CaMKIV plays a pivotal role in blood pressure regulation through the control of endothelial nitric oxide synthase activity.
The 2008 World Health Organization (WHO) classification of hematopoietic and lymphoid tissues has been recently revised, and publication of the updated 2016 version is expected soon. Given that ...cytopathologists are often involved in the diagnosis of primary, recurrent, and transformed lymphoproliferative disorders, knowledge of updates to the WHO lymphoma classification, including terminology, pathogenesis, ancillary techniques, and targeted therapies is necessary. Herein, we reference the last decade of cytology specific literature for seven newer B‐cell disorders and provide illustrative examples of each entity from our files.
Fellowship recruitment and retention of a skilled workforce is one of the biggest challenges that not only cytopathology is facing but that the field of pathology in general is being confronted with. ...There have long been issues with the fellowship recruitment process for both applicants and fellowship directors, including pressure to move the application process earlier and earlier and frustrations stemming from applicants needing to determine different individual timelines and program requirements. The unified timeline for fellowship recruitment was established as an attempt to standardize the recruitment process and to address the key issues of the push for earlier and earlier decision-making, which placed significant anxiety on trainees, as well as the burden on programs of more unexpected openings. While institution of the unified timeline has had many successes, there have been problems as well. Here, we discuss the multifaceted and intertwined factors that affect fellowship recruitment with a review of the historical context and the current setting and with an eye towards future directions. In the end, the issues we are currently facing are complex and there is likely no perfect solution to fixing an inherently broken system. However, the ultimate goal should be in better supporting our trainees’ development and promoting a more fair and equitable recruitment process. Only by working together can we optimize the process for both applicants and programs alike.
•The unified timeline for fellowship recruitment was an attempt to add more standardization to the recruitment process and to address some of the key issues including the push for earlier and earlier decision-making, which placed significant anxiety on residents, as well as the burden of more unexpected openings on programs.•The unified timeline has had many successes, but there have been issues as well; these issues reflect a complex interplay of different underlying issues that are plaguing not only the field of cytopathology but the field of pathology in general.•We herein discuss the issues complicating fellowship recruitment currently. We review the historical setting in order to add context to the current climate. We also discuss possibilities going forward.
The aim of this study was to test the hypothesis that our 60-gene DNA/RNA ThyroSeq v2 next-generation sequence (NGS) assay would identify additional genetic markers, including gene fusions in ...sporadic pediatric differentiated thyroid carcinomas (DTC) that had no known molecular alterations. Sporadic pediatric DTCs with informative molecular testing (n = 18) were studied. We previously tested 15 cases by our standard 7-gene (BRAF, NRAS, HRAS, KRAS, RET/PTC1, RET/PTC3, PAX8/PPARg) mutation panel. Three cases were not tested previously. The standard 7-gene panel identified molecular alterations in 9 of 15 tumors (60%). Cases analyzed by ThyroSeq v2 NGS included the six previously negative cases by the standard 7-gene panel and three cases not previously tested. The NGS assay revealed new gene fusions in four of six previously negative cases (67%). These gene fusions included ETV6/NTRK3 (n = 3) and TPR/NTRK1 (n = 1). A point mutation (BRAF-V600E) was detected in one of three untested cases. While standard testing could identify only molecular alterations in 60% of cases, with the addition of the ThyroSeq v2 NGS, this increased to 87% (n = 13/15). Some cases with chromosomal rearrangements, including ETV6/NTRK3, appear to be associated with an aggressive histopathologic phenotype, but had no documented history of radiation exposure. Additional work is needed to investigate if pediatric DTCs could benefit from a reclassification based on molecular subtypes, which may better reflect their underlying biologic potential. Our data support the use of broad gene panels for the molecular diagnostics of pediatric thyroid nodules to aid future classification, treatment, and clinical management recommendations.
The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) provides a reporting scheme for thyroid fine needle aspiration (FNA) and includes three indeterminate categories with different ...management strategies. This study analyzes indeterminate thyroid FNAs in children, and correlates these findings with the histological features.
A total of 179 thyroid FNA specimens were retrieved from children. Cases were categorized by TBSRTC. Only cases diagnosed as atypia (AUS)/follicular lesion of undetermined significance (FLUS), suspicious for follicular or oncocytic neoplasm (SFON), or suspicious for malignancy (SM) were selected and correlated with the nodule size and histological follow-up.
Sixty-eight cases were identified, including 43 (63%) AUS/FLUS diagnoses, 19 (28%) SFON, and 6 (9%) SM. On follow-up, 48% were malignant, including 28% AUS/FLUS cases, 58% SFON, and 100% SM. The average size of the malignant lesions diagnosed preoperatively as AUS/FLUS was 1.5 cm (range 0.7-4.5), compared to 3.3 cm (range 1.2-6.6) in SFON and 2.8 cm (range 0.7-3.8) in SM. Malignancies included 92% papillary thyroid carcinoma (PTC), 77% of which were the follicular variant of PTC (FVPTC) and 8% follicular carcinomas. The AUS/FLUS cases were largely due to compromised specimens (49%) and the highest malignancy rate occurred in those with cytological atypia (50%).
This study shows an incremental risk of malignancy within the indeterminate categories using TBSRTC in children. Malignant nodules with a preoperative AUS/FLUS diagnosis tended to be smaller than those with a SFON or SM diagnosis, and the vast majority of malignancies were PTC, with a high proportion being FVPTC.
Thyroid nodules are less common in children than adults, but the risk of malignancy in thyroid nodules is much higher in children. The ability to characterize pediatric thyroid nodules has improved ...with the use of ultrasound-guided fine-needle aspiration, the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) classification system, and expanded molecular testing. Nevertheless, stratification criteria to predict thyroid malignancy in children are poorly defined. Our objective was to determine if clinical presentation and molecular genetics could predict malignancy in pediatric thyroid nodules.
Retrospective chart review of patients ≤18 years of age at the Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center with the diagnosis of a thyroid nodule from January 2007 to January 2012 was conducted. Eighty-nine subjects fulfilled the inclusion criteria: 1) thyroid nodule ≥0.8 cm and biopsy (n=76), or 2) thyroid nodule ≥0.8 cm, no biopsy, and ultrasound follow-up for at least 2 years (n=13).
Twenty-four (27%) of 89 patients were diagnosed with thyroid cancer (50% papillary thyroid carcinoma PTC, 50% follicular variant of papillary thyroid carcinoma FVPTC). Features associated with malignancy included larger nodule size, palpable nodule, or palpable lymphadenopathy. There were no differences in presenting features between patients with PTC and those with FVPTC. Thyroid malignancy was diagnosed in all nine patients with a molecular abnormality (BRAF, RAS, RET/PTC, PAX8/PPARγ).
Clinical features, FNA cytology, and molecular genetics are valuable tools to discriminate benign from malignant nodules in pediatric patients. This information is important to direct subsequent clinical management.
Pleural effusions, when benign, are attributed to cardiac events and suffusion of fluid within the pleural space. When malignant, lymphatic obstruction by tumor and failure to absorb constitutively ...produced fluid is the predominant formulation. The prevailing view has been challenged recently, namely that the lymphatics are only passive vessels, carrying antigenic fluid to secondary lymphoid sites. Rather, lymphatic vessels can be a selective barrier, efficiently coordinating egress of immune cells and factors within tissues, limiting tumor spread and immune pathology. An alternative explanation, offered here, is that damage associated molecular pattern molecules, released in excess, maintain a local milieu associated with recruitment and retention of immune cells associated with failed lymphatic clearance and functional lymphatic obstruction. We found that levels of high mobility group box 1 (HMGB1) were equally elevated in both benign and malignant pleural effusions (MPEs) and that limited diversity of T cell receptor expressing gamma and delta chain were inversely associated with these levels in MPEs. Acellular fluid from MPEs enhanced γδ T cell proliferation
, while inhibiting cytokine production from γδ T cells and monocytes as well as restricting monocyte chemotaxis. Novel therapeutic strategies, targeting HMGB1 and its neutralization in such effusions as well as direct delivery of immune cells into the pleural space to reconstitute normal physiology should be considered.
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