Bcl–2 is an anti-apoptotic protein with important roles in vascular homeostasis and angiogenesis. Mice globally lacking Bcl–2 (Bcl–2 -/-) are small in stature and succumb to renal failure shortly after weaning as a result of renal hypoplasia/cystic dysplasia. We have shown that Bcl–2 -/- mice displayed attenuated retinal vascular development and neovascularization. In vitro studies indicated that in addition to modulating apoptosis, Bcl–2 expression also impacts endothelial and epithelial cell adhesion, migration and extracellular matrix production. However, studies delineating the cell autonomous role Bcl–2 expression plays in the endothelium during vascular development, pruning and remodeling, and neovascularization are lacking. Here we generated mice carrying a conditional Bcl–2 allele (Bcl-2Flox/Flox) and VE-cadherin-cre (Bcl-2EC mice). Bcl-2EC mice were of normal stature and lifespan and displayed some but not all of the retinal vascular defects previously observed in global Bcl–2 deficient mice. Bcl-2EC mice had decreased numbers of endothelial cells, decreased retinal arteries and premature primary branching of the retinal vasculature, but unlike the global knockout mice, spreading of the retinal superficial vascular layer proceeded normally. Choroidal neovascularization was attenuated in Bcl-2EC mice, although retinal neovascularization accompanying oxygen-induced ischemic retinopathy was not. Thus, Bcl–2 expression in the endothelium plays a significant role during postnatal retinal vascularization, and pathological choroidal but not retinal neovascularization, suggesting vascular bed specific Bcl–2 function in the endothelium.
A 40-year-old woman presented to the Brooke Army Medical Center Emergency Department complaining of 2 episodes of gross hematuria. Computed tomography and intravenous pyelogram revealed a right renal mass. A radical nephrectomy was performed with complete excision of the mass with negative margins on histological examination. The patient was diagnosed with renal medullary carcinoma, Fuhrman grade 4, based upon histological examination. A positron emission tomography scan revealed no other evidence of the disease. The pathologic stage was stage I renal medullary carcinoma. Four months after her nephrectomy, the patient developed a papule on her right frontal scalp. Initially thought to be a cyst, the papule increased in size over the course of 2 months and eventually ulcerated. At that time, she presented to the Wilford Hall Medical Center Dermatology Clinic with a 2.5-cm ulcerated tumor with pink rolled borders. A punch biopsy of the tumor revealed an infiltrating carcinoma with scattered glandular lumina and desmoplastic and mucinous stroma. The carcinoma was completely intradermal. Expert consultation confirmed the diagnosis of metastatic renal medullary carcinoma. Clear cell (conventional) and papillary renal cell carcinomas are known to metastasize to the skin, including the scalp. Renal medullary carcinoma commonly metastasizes to the regional lymph nodes, lung, liver, or adrenals. To our knowledge, this is the first report of a cutaneous metastasis of renal medullary carcinoma.
Apoptosis plays a central role in developmental and pathological angiogenesis and vessel regression. Bim is a pro-apoptotic Bcl-2 family member that plays a prominent role in both developmental and pathological ocular vessel regression, and neovascularization. Endothelial cells (EC) and pericytes (PC) each play unique roles during vascular development, maintenance and regression. We recently showed that germline deletion of Bim results in persistent hyaloid vasculature, increased retinal vascular density and prevents retinal vessel regression in response to hyperoxia. To determine whether retinal vascular regression is attributable to Bim expression in EC or PC we generated mice carrying a conditional Bim allele (BimFlox/Flox) and VE-cadherin-cre (BimEC mice) or Pdgfrb-cre (BimPC mice). BimEC and BimPC mice demonstrated attenuated hyaloid vessel regression and postnatal retinal vascular remodeling. We also observed decreased retinal vascular apoptosis and proliferation. Unlike global Bim -/- mice, mice conditionally lacking Bim in EC or PC underwent hyperoxia-mediated vessel obliteration and subsequent retinal neovascularization during oxygen-induced ischemic retinopathy similar to control littermates. Thus, understanding the cell autonomous role Bim plays in the retinal vascular homeostasis will give us new insight into how to modulate pathological retinal neovascularization and vessel regression to preserve vision.
Straightforwardm ethods for detecting adenosine-to-inosine (A-to-I) RNA editinga re key to ab etter understanding of its regulation, function, and connection with disease. Wea ddress this need by developing an ovel reagent, N-(4-ethynylphenyl)acrylamide (EPhAA), and illustrating its ability to selectively label inosine in RNA. EPhAA is synthesized in as ingle step, reacts rapidlyw ith inosine, and is "click"-compatible, enabling flexible attachment of fluorescent probesa te diting sites. We first validate EPhAA reactivity and selectivityf or inosine in both ribonucleosides and RNA substrates, and then apply our approach to directly monitor in vitro A-to-I RNA editing activity using recombinantA DAR enzymes. This method improves upon existing inosine chemical-labeling techniques and provides ac ost-effective, rapid, and non-radioactive approach for detecting inosine formation in RNA. We envision this method will improve the study of A-to-I editing and enable better characterization of RNA modification patterns in different settings. RNA is chemically modified by anumber of enzymes after transcription, in turn influencing RNA stability, localizationa nd activity within the cell. Adenosine-to-inosine (A-to-I) RNA editing is one of the most widespread modifications, and is performed by adenosine deaminases acting on RNA (ADARs) (Scheme 1a). [1] Adenosine deaminationc hanges the molecular structurea nd hydrogen-bonding pattern of the nucleobase, and resulting inosines insteadb ase pairw ith cytidinet oe ffectively recode these sites as guanosine. Editings ites within protein-coding mRNAsd irectly alter amino acid sequences and produce different protein isoforms. Non-coding RNAs also undergo extensive editing, including microRNAs and small-interfering RNAs, significantly alteringt heir biosynthesis, localization, and gene regulation properties. [2-3] A-to-I editing is essential for an umber of biological processes including tissue development, [4-5] neurologicalf unction, [6] and immune system activation. [7] Dysfunctional editing is also directlyl inked with autoimmune diseases, [8-9] neurological disorders, [10] and several types of cancer. [11-12] Despite this importance,o ur overall understanding of A-to-I editingr egulation is limited. In particular,w hile many sites have been identified (> 5million), [13-14] it is unclear why certain sites are edited at higherf requency than others and what precise function they each serve. [15] Efforts to map A-to-I locations and ADAR binding sites have revealed that editingp atterns are highly complex and variable in humans, [7, 16-18] and the precise mechanismsb yw hich ADAR enzymes bind to and edit specific RNA sequences remain unclear.T his gap is also significant for therapeutic site-directed RNA editing strategies, [19] as both the design and precise implementation of this machinery is reliant on at horough understanding of ADAR regulation. Detecting inosine formation in RNA is of central importance for characterizing editingm echanisms. While high-throughput RNA sequencin...
The vast majority of patients 75 years and older undergoing Mohs surgery are highly functioning. Lower functioning patients are older with larger symptomatic tumors that negatively impact their lives.
The outpatient setting remains a cost-effective location to treat skin cancer compared with the operating room.
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