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Application of counter-selectable marker PIGA in engineering designer deletion cell lines and characterization of CRISPR deletion efficiency

Li, Donghui; Sun, Xiaoji; Yu, Fangzhou; Perle, Mary Ann; Araten, David; Boeke, Jef D
The CRISPR/Cas9 system is a technology for genome engineering, which has been applied to indel mutations in genes as well as targeted gene deletion and replacement. Here, we describe paired gRNA deletions along the PIGA locus on the human X chromosome ranging from 17 kb to 2 Mb. We found no compelling linear correlation between deletion size and the deletion efficiency, and there is no substantial impact of topologically associating domains on deletion frequency. Using this precise deletion technique, we have engineered a series of designer deletion cell lines, including one with deletions of two X-chromosomal counterselectable (negative selection) markers, PIGA and HPRT1, and additional cell lines bearing each individual deletion. PIGA encodes a component of the glycosylphosphatidylinositol (GPI) anchor biosynthetic apparatus. The PIGA gene counterselectable marker has unique features, including existing single cell level assays for both function and loss of function of PIGA and the existence of a potent counterselectable agent, proaerolysin, which we use routinely for selection against cells expressing PIGA. These designer cell lines may serve as a general platform with multiple selection markers and may be particularly useful for large scale genome engineering projects such as Genome Project-Write (GP-write).
PMID: 33591308
ISSN: 1362-4962
CID: 4786642

An Unusual Cause of Cardiac Tamponade: Primary Pericardial Synovial Sarcoma [Case Report]

Saba, Shahryar G; Ren, Qinghu; Perle, Mary Ann
PMID: 33511808
ISSN: 2586-7296
CID: 4767652

Rapid and robust reversion to essential thrombocythemia on treatment with Decitabine in a case of hydroxyurea-induced t-MDS/AML

Horton, Joshua D; Arbini, Arnaldo A; Perle, Mary Ann; Raphael, Bruce G
Rapid remission of MDS/AML may be induced with Decitabine; however, significant megakaryocyte expansion and subsequent thrombocytosis may occur. Decitabine-mediated reversion of the MDS to benign ET via hypomethylation of JAK/STAT pathway repressors is one potential mechanism to explain this observed phenomenon.
PMCID:4706408
PMID: 26783435
ISSN: 2050-0904
CID: 1921402

Personalization of cancer treatment using predictive simulation

Doudican, Nicole A; Kumar, Ansu; Singh, Neeraj; Nair, Prashant R; Lala, Deepak A; Basu, Kabya; Talawdekar, Anay A; Sultana, Zeba; Tiwari, Krishna; Tyagi, Anuj; Abbasi, Taher; Vali, Shireen; Vij, Ravi; Fiala, Mark; King, Justin; Perle, MaryAnn; Mazumder, Amitabha
BackgroundThe personalization of cancer treatments implies the reconsideration of a one-size-fits-all paradigm. This move has spawned increased use of next generation sequencing to understand mutations and copy number aberrations in cancer cells. Initial personalization successes have been primarily driven by drugs targeting one patient-specific oncogene (e.g., Gleevec, Xalkori, Herceptin). Unfortunately, most cancers include a multitude of aberrations, and the overall impact on cancer signaling and metabolic networks cannot be easily nullified by a single drug.MethodsWe used a novel predictive simulation approach to create an avatar of patient cancer cells using point mutations and copy number aberration data. Simulation avatars of myeloma patients were functionally screened using various molecularly targeted drugs both individually and in combination to identify drugs that are efficacious and synergistic. Repurposing of drugs that are FDA-approved or under clinical study with validated clinical safety and pharmacokinetic data can provide a rapid translational path to the clinic. High-risk multiple myeloma patients were modeled, and the simulation predictions were assessed ex vivo using patient cells.ResultsHere, we present an approach to address the key challenge of interpreting patient profiling genomic signatures into actionable clinical insights to make the personalization of cancer therapy a practical reality. Through the rational design of personalized treatments, our approach also targets multiple patient-relevant pathways to address the emergence of single therapy resistance. Our predictive platform identified drug regimens for four high-risk multiple myeloma patients. The predicted regimes were found to be effective in ex vivo analyses using patient cells.ConclusionsThese multiple validations confirm this approach and methodology for the use of big data to create personalized therapeutics using predictive simulation approaches.
PMCID:4320499
PMID: 25638213
ISSN: 1479-5876
CID: 1522102

Clear cell sarcoma of the penis: a case report

Ito, Timothy; Melamed, Jonathan; Perle, Mary Ann; Alukal, Joseph
Clear cell sarcoma of the penis is exceedingly rare with only one prior case involving the penis reported in the literature. We present the case of a 32 year old male who presented with an infiltrative neoplasm at the base of the penis as well as extensive metastatic disease to the lymph nodes and bone. Morphologic, immunohistochemical and cytogenetic findings established the diagnosis of clear cell sarcoma. Despite chemotherapy the patient's disease was rapidly progressive and the patient died of disease within 8 months of diagnosis.
PMCID:4446382
PMID: 26069887
ISSN: 2330-1910
CID: 1626702

Heterogeneity of Stem Cells in Human Amniotic Fluid

Chen, Zhisheng; Chan, Michael K; Strelchenko, Nicholas; Wang, Fang; Liu, Li; Perle, Mary Ann; Basch, Ross S; Young, Bruce K
Amniotic fluid contains a mixture of cells with capacity to differentiate into all germ layers. These cells are present in large numbers in midtrimester samples obtained for cytogenetic diagnosis, and have been identified by stem cell surface markers and transcription factors. We studied cultured samples from patients who had both direct cultures and matched cultures obtained 2 weeks later from the cytogenetics laboratory as well as patients with cytogenetics material only. Samples were cryogenically frozen, thawed, expanded in culture with excellent viability. There was considerable individual variation unrelated to gestational age or telomere length. Phenotype for embryonic markers was assessed by flow cytometry and by quantitative polymerase chain reaction. The most consistently present stem cell markers in substantial amounts were CD90, SSEA-4, & TRA-1-60. Cells with CD90, SSEA-4 & TRA-1-60 double and triple labeled also could be identified and subcultured, confirming the heterogeneity of the amniotic fluid stem cell population
ORIGINAL:0010515
ISSN: 2325-9620
CID: 1908162

Trisomy 8 in myeloid leukemia cutis confirmed by fluorescence in situ hybridization analysis

Shvartsbeyn, Marianna; Meehan, Shane M; Gu, Ping; Nierodzik, Mary Lynn; Perle, Mary Ann
We present a case of a 64-year-old man with refractory acute myeloid leukemia and trisomy 8 who developed leukemia cutis. Interphase fluorescence in situ hybridization (FISH) was performed on a paraffin-embedded skin section. FISH confirmed a population of cells with trisomy 8 in the blastic infiltrates involving the skin. This case illustrates a novel application of interphase FISH to confirm the diagnosis of leukemia cutis.
PMID: 22882450
ISSN: 0303-6987
CID: 180076

Characteristics of chromosomal abnormalities diagnosed after spontaneous abortions in an infertile population

Werner, Marie; Reh, Andrea; Grifo, Jamie; Perle, Mary Ann
PURPOSE: To estimate the prevalence of chromosomally abnormal related miscarriages in an infertile population. METHODS: Retrospective analysis of cytogenetics obtained by chorionic villi harvesting of the first miscarriage cycle of infertile patients at our center from 2001-2010 were reviewed. Abnormal results were characterized as trisomy, monosomy X, structural, or other. Age, # of eggs, #2PN, # embryos transferred, day of transfer, and performance of intracytoplasmic sperm injection (ICSI) were recorded. RESULTS: In a study population of 299 patients with a mean age of 38.0 +/- 4.5 y, 276(92 %) patients had some form of assisted reproductive technologies (ART), and 244(82 %) had IVF. Of all results, 71.6 % had an abnormal karyotype. Patients with abnormal cytogenetics were older (38.6 +/- 4.1 vs. 36.3 +/- 4.9, p < 0.001), and more likely to have a day 3 transfer (age < 38 ( 20.7 %) vs. age 38 (46.3 %), p = <0.001) with more embryos transferred (3.0 +/- 1.2, vs. 2.3 +/- 0.9, p < 0.001). The performance of ICSI did not affect the rate of cytogenetically abnormal products of conception (ICSI 68.3 % vs. no ICSI 70.7 %). In comparing patients, monosomy X was more common in <38 y. Rates of trisomy, although not statistically significant, were higher in older patients. CONCLUSIONS: The classic associations between advancing age and chromosomal abnormalities, and younger age and monosomy X, are affirmed in our infertile population. There was no increase in chromosomal abnormalities in cycles where ICSI was performed. Older patients are more likely to have day 3 transfers and more embryos transferred. Our chromosomal abnormality rates are higher than classic estimates but comparable to recent studies. The limitation of this study was a lack in uniformity among practitioners in recommending all patients have a Dilation and Curettage (D&C) at time of diagnosis. Such information may serve to improve the counseling of patients after miscarriage.
PMCID:3430785
PMID: 22618194
ISSN: 1058-0468
CID: 177018

Primary pericardial synovial sarcoma: A rare case report with FISH analysis and review of literature [Meeting Abstract]

Ren, Q; Saba, S G; Heo, S; Rosenzweig, B P; Srichai, M B; Perle, M A
Primary cardiac synovial sarcoma is a rare malignancy, comprising approximately 5% of cardiac sarcomas and fewer than 0.1% of all primary cardiac tumors. Synovial sarcoma is typically characterized by a t(X;18)(p11.2;q11.2) translocation resulting in fusion of the SS18 (aka SYT) gene on chromosome 18 with the SSX1, 2, or 4 genes on the X chromosome.We report a case of primary pericardial synovial sarcoma in a 42-year-old man with dyspnea. Imaging studies showed an 8.0 x 4.8 cm enhancing pericardial mass compressing the left atrium and a large pericardial effusion with compression effect consistent with tamponade. The patient underwent partial surgical resection of the mass. Histologic examination revealed an invasive malignant neoplasm with fascicles and sheets of uniform spindle cells with pleomorphic nuclei and many mitoses (7 per 10 HPF). This monophasic pattern raises a differential diagnosis including synovial sarcoma, fibrosarcoma, epithelial sarcoma, and leiomyosarcoma. The diagnosis of synovial sarcoma was confirmed by interphase FISH on FFPE tissue with an SS18 break-apart probe that was positive for an SS18 rearrangement. The patient underwent adjuvant chemotherapy and radiotherapy. He survives at 9 months after diagnosis with residual tumor growing rapidly. A review of the literature reveals 40 case reports of primary synovial sarcoma of the heart. The mean age is 36 years with a M/F ratio of 2.25. The most common locations are pericardium (13 cases) and right atria (12). Seventeen cases are monophasic type, of which 11 have confirmed t(X;18) translocations by cytogenetics, FISH, and/or RT-PCR. The prognosis is poor; 11 patients died during the first year after diagnosis. FISH provides a valuable tool for the diagnosis of synovial sarcoma, especially for challenging cases in uncommon locations (eg, heart). Identification of patients with the SS18 translocation is important for future targeted therapies
EMBASE:70890052
ISSN: 0002-9173
CID: 179309

Development of five new melanoma low passage cell lines representing the clinical and genetic profile of their tumors of origin [Letter]

de Miera, Eleazar Vega-Saenz; Friedman, Erica B; Greenwald, Holly S; Perle, Mary A; Osman, Iman
PMCID:3329580
PMID: 22404973
ISSN: 1755-1471
CID: 164344