Publications by authors named "Liwei Jia"

30 Publications

  • Page 1 of 1

Adrenal Cortical Carcinoma and Additional Rare Pathologic Findings in Multi-Organs in a Birt-Hogg-Dubé Syndrome Patient: With an Emphasis on the Molecular Characteristics of Adrenal Cortical Carcinoma.

Int J Surg Pathol 2022 Aug 9:10668969221117246. Epub 2022 Aug 9.

Department of Pathology, 89063UT Southwestern Medical Center, Dallas, TX, USA.

Birt-Hogg-Dubé (BHD) syndrome is a rare autosomal dominant disorder caused by germline alterations in the gene. We report a 38-year-old man with BHD syndrome presenting with multiple rare pathologic findings involving various organs, including adrenal cortical carcinoma (ACC). Initially, he presented with severe cholestatic jaundice and was found to have a 25 cm left adrenal mass with radiologic evidence of lung metastases, which was diagnosed as ACC on resection. Concurrently, pigmented, bile-stained granular casts were present within the kidney and diffuse cholestasis of the liver consistent with Stauffer syndrome was identified. Subsequent staging workup detected a 1.2 cm tubulovillous adenoma in the distal ascending colon and an incidental 1.2 cm thyroid nodule. Germline genetic testing revealed a pathogenic c.1285dup. Targeted DNA next generation sequencing of ACC revealed c.1285dup, c.5332C>T, c.1074del, and c.3282C>A and concurrent transcriptomic analysis demonstrated overexpression. Fourteen months after resection, follow-up computerized tomography (CT) identified the progression of lung metastases and chemotherapy with etoposide doxorubicin and cisplatin was initiated. Here, we report the first ACC with the molecular characteristics in a BHD syndrome patient, although 5 adrenal lesions, including ACC, adenomas or neoplasm with malignant potential due to higher Ki67 labelling index, have been reported in the literature and no somatic analysis in these tumors were performed. Despite the rarity, our case potentially expands the tumor spectrum of BHD patients, helps to solidify possible association with adrenal cortical tumors and reiterates the value of genetic counseling in patients with ACC.
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http://dx.doi.org/10.1177/10668969221117246DOI Listing
August 2022

Severe Cholestatic Jaundice (Stauffer Syndrome) as a Rare Paraneoplastic Manifestation in Adrenocortical Carcinoma.

J Endocr Soc 2022 Aug 29;6(8):bvac101. Epub 2022 Jun 29.

Division of Endocrinology and Metabolism, UT Southwestern Medical Center, Dallas, Texas 75390, USA.

Background: Adrenocortical carcinoma (ACC) is a rare malignancy arising from the adrenal cortex. While ACC can be associated with adrenal hormone excess syndromes, classic paraneoplastic syndromes are rarely seen. Stauffer syndrome, a paraneoplastic phenomenon characterized by reversible cholestasis in the absence of liver metastases, has been described with renal carcinoma and other malignancies but has not been previously reported in ACC.

Case Presentation: A 38-year-old man presented with emesis, painless jaundice, pruritus, and weight loss. Laboratory evaluation demonstrated elevated total bilirubin of 8.7 mg/dL (N < 1.3 mg/dL). Computed tomography revealed a 20.4-cm left adrenal mass without evidence of liver metastases. The patient's condition deteriorated rapidly with progressive renal failure and worsening hyperbilirubinemia. The patient underwent left adrenalectomy, nephrectomy, ureterolysis, and wedge liver biopsy. Histopathology showed necrotic ACC with tumor invasion into the adrenal capsule, no lymphovascular invasion, uninvolved margins, and Ki-67 of 40%. Kidney parenchyma exhibited diffuse pigment casts. The liver specimen contained diffuse bile deposits and minimal chronic inflammation in the portal tracts. He tested positive for the pathogenic variant of () gene consistent with Birt-Hogg-Dube syndrome. Renal function recovered after surgery, and bilirubin level normalized after several weeks. Based on clinical presentation and absence of other etiologies, reversible cholestatic jaundice was attributed to Stauffer syndrome.

Conclusion: This is the first report of a unique presentation of paraneoplastic-related hyperbilirubinemia in the setting of ACC. While extremely rare, Stauffer syndrome should still be considered in differential diagnosis in patients with ACC with liver dysfunction and jaundice without evidence of liver metastases.
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http://dx.doi.org/10.1210/jendso/bvac101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9261502PMC
August 2022

An oncogenic JMJD6-DGAT1 axis tunes the epigenetic regulation of lipid droplet formation in clear cell renal cell carcinoma.

Mol Cell 2022 Jun 15. Epub 2022 Jun 15.

Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address:

Characterized by intracellular lipid droplet accumulation, clear cell renal cell carcinoma (ccRCC) is resistant to cytotoxic chemotherapy and is a lethal disease. Through an unbiased siRNA screen of 2-oxoglutarate (2-OG)-dependent enzymes, which play a critical role in tumorigenesis, we identified Jumonji domain-containing 6 (JMJD6) as an essential gene for ccRCC tumor development. The downregulation of JMJD6 abolished ccRCC colony formation in vitro and inhibited orthotopic tumor growth in vivo. Integrated ChIP-seq and RNA-seq analyses uncovered diacylglycerol O-acyltransferase 1 (DGAT1) as a critical JMJD6 effector. Mechanistically, JMJD6 interacted with RBM39 and co-occupied DGAT1 gene promoter with H3K4me3 to induce DGAT1 expression. JMJD6 silencing reduced DGAT1, leading to decreased lipid droplet formation and tumorigenesis. The pharmacological inhibition (or depletion) of DGAT1 inhibited lipid droplet formation in vitro and ccRCC tumorigenesis in vivo. Thus, the JMJD6-DGAT1 axis represents a potential new therapeutic target for ccRCC.
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http://dx.doi.org/10.1016/j.molcel.2022.06.003DOI Listing
June 2022

Management of Testicular Germ Cell Tumor With Somatic-Type Malignancy.

Oncology (Williston Park) 2022 06;36(6):375-377

A man, aged 21 years, presented with a 4-month history of progressive swelling of the right testicle. Ultrasound revealed a heterogenous solid mass in the right testicle suspicious for malignancy. Further work-up included CT scans, which identified a 2-cm retroperitoneal lymph node; there was no evidence of thoracic metastases. Serum tumor markers revealed a mildly elevated α-fetoprotein (AFP) and normal lactate dehydrogenase (LDH) and human chorionic gonadotropin (hCG). The patient underwent right radical inguinal orchiectomy. Pathology evaluation demonstrated 1% teratoma with extensive secondary somatic-type malignant components of embryonal rhabdomyosarcoma and chondrosarcoma. No lymphovascular invasion was identified. Repeat tumor markers showed normal AFP, LDH, and hCG. Follow-up short-interval CT scans confirmed a dominant 2-cm interaortocaval lymph node with no evidence of distant metastases. The patient underwent retroperitoneal lymph node dissection, which revealed 1 of 24 lymph nodes positive for similar somatic-type malignancy composed of rhabdomyosarcoma and chondrosarcoma as well as undifferentiated spindle cell sarcoma with extranodal extension. Immunohistochemistry revealed that tumor cells were positive for myogenin and desmin and negative for SALL4.
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http://dx.doi.org/10.46883/2022.25920962DOI Listing
June 2022

The isomers, aloe-emodin and emodin, possess differential inhibitory activities against CYP1B1 enzyme.

Steroids 2022 Sep 2;185:109055. Epub 2022 Jun 2.

School of Pharmacy, Heilongjiang University of Chinese Medicine, NO. 24 Heping Road, Harbin 150040, PR China.

Aloe-emodin, known as a 3-hydroxymethyl-chrysazin, is one of anthraquinones mainly found in Rheum officinale Baill, Rheum palmatum L and Rheum tanguticum Maxim. Ex BALF. In recent studies, aloe-emodin possesses many pharmacological effects, including antitumor, antibacterial, antiviral, anti-inflammatory, cardiovascular protection, liver protection, immune regulation, estrogenic activity as a phytoestrogen, and so on. Cytochrome P450 (CYP) 1B1 (CYP1B1), as a major estrogen metabolizing enzyme, can metabolize 17β-estradiol (E2) to 4-hydroxy-E2 (4-OH-E2), which cause DNA damage and lead to tumor. Few studies have found that anthraquinones possess inhibitory activity against CYP1B1 enzyme. In this study, compared with emodin (3-Hydroxy-6-methyl-chrysazin, CHO), the inhibition of aloe-emodin (3-hydroxymethyl-chrysazin, CHO) on the activity of CYP1B1 was studied. The molecular mechanism of inhibition and the structure-activity relationship were also discussed. Although isomeric, the IC50 values of aloe-emodin and emodin were 0.192 ± 0.015 nM and 0.067 ± 0.003 µM, indicating the inhibition of aloe-emodin was about 350times stronger than that of emodin. Through structure-activity relationship analyses, it revealed the difference of inhibitory activity only due to different hydroxyl positions. When the hydroxyl group is transferred from the chrysazin skeleton to the methyl group, the hydrogen bond formed by this structure with the CYP1B1 protein can change the protein conformation, which may interfere with the binding of the substrate to CYP1B1 protein active site pocket and inhibit the catalytic activity of the CYP1B1 protein. Although the hydroxyl position changed, the inhibition mechanism did not change, all of which were mixed inhibition. This study reveals an anti-tumor mechanism of the anthraquinone compound aloe-emodin.
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http://dx.doi.org/10.1016/j.steroids.2022.109055DOI Listing
September 2022

PSA density is associated with BPH cellular composition.

Prostate 2022 Sep 2;82(12):1162-1169. Epub 2022 Jun 2.

Department of Urology, UT Southwestern Medical Center, Dallas, Texas, USA.

Background: Current AUA guidelines recommend 5 alpha reductase inhibitor (5ARI) treatment for patients with obstructive benign prostatic hyperplasia (BPH) that display prostate volume ≥30 cc and total prostate specific antigen (PSA) ≥1.5 ng/ml. However, BPH is highly pleomorphic and response to 5ARIs is highly variable. An understanding of cellular composition based on a noninvasive PSA density test could lead to improved clinical decision making.

Methods: The histological composition of 307 BPH specimens was scored by a pathologist for stromo-glandular content and associated with total PSA, prostate volume, PSA density and other clinical variables using univariate and multivariate linear regression.

Results: The percentage of glandular composition in prostates of 5ARI-naïve men was positively and independently associated with PSA and PSA density. It was determined through statistical modeling that a PSA density ≤0.05 ng/ml associated with a glandular composition of ≤30% with 76% sensitivity.

Conclusions: PSA density could provide a decisive variable for estimating BPH cellular content and may eventually improve selection of patients for 5ARI treatment. Further work is needed to demonstrate that patients with higher glandular content are more responsive to 5ARI treatment.
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http://dx.doi.org/10.1002/pros.24367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9329225PMC
September 2022

Incidental Solitary Adrenal Metastasis as the Initial Manifestation of a Solid Variant of Papillary Thyroid Carcinoma, With Emphasis on Pathologic Diagnosis and Clinical Management.

AACE Clin Case Rep 2022 May-Jun;8(3):131-134. Epub 2022 Jan 13.

Division of General Surgery, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas.

Objective: Distant metastases from papillary thyroid carcinoma (PTC) are relatively rare and may be associated with a poor prognosis. The adrenal gland is a highly unusual site of metastasis in the natural course of PTC. Herein, we describe a case of an incidentally detected metastatic solid variant of PTC in the adrenal gland of an asymptomatic patient as the initial presentation.

Case Report: A 67-year-old male patient was evaluated for a 4.7-cm adrenal incidentaloma discovered during a workup for nephrolithiasis. Biochemical evaluation revealed a nonfunctioning adrenal mass. The patient underwent adrenalectomy, which revealed metastatic PTC. A subsequent thyroid ultrasound revealed an isthmic nodule. Fine needle aspiration of the nodule was cytologically suspicious for a follicular neoplasm, and gene expression analysis revealed an c.182A>G sequence variation. The patient subsequently underwent total thyroidectomy, which revealed a 1.2-cm solid variant of PTC in the thyroid isthmus. Postoperatively, the patient underwent radioactive iodine ablation.

Discussion: Our case illustrates an exceedingly rare and challenging situation-a metastatic solid variant of PTC in the adrenal gland of a patient with no prior history of PTC. When confronted with a PTC in the adrenal gland in the absence of a previously identified primary tumor, our experience suggests that the next step in management should be total thyroidectomy followed by radioactive iodine ablation.

Conclusion: A solid variant of PTC is a rare cause of an incidentally detected adrenal lesion. Multidisciplinary care team coordination is essential for accurate diagnosis and treatment plan formulation.
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http://dx.doi.org/10.1016/j.aace.2022.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9123585PMC
January 2022

Amplification in Epithelioid Angiosarcoma of the Urinary Bladder and Prostate Following Prostate Radiotherapy: A Case Report with a Novel Molecular Alteration.

Int J Surg Pathol 2022 Feb 21:10668969221081740. Epub 2022 Feb 21.

89063Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Epithelioid angiosarcoma is a rare variant of angiosarcoma. Radiation-associated epithelioid angiosarcoma of the urinary bladder and prostate is an exceedingly rare tumor and there are only 8 cases of epithelioid angiosarcoma of the urinary bladder and prostate associated with previous radiotherapy in the literature. To the best of our knowledge, gene amplification has not been previously reported in epithelioid angiosarcoma of the urinary bladder and prostate following radiotherapy, although it is observed in radiation-associated angiosarcoma of other anatomic sites. Here we report the first case of epithelioid angiosarcoma of the urinary bladder and prostate with gene amplification detected by fluorescence in situ hybridization (FISH) analysis in a 70-year-old male patient 10 years after receiving radiation and hormonal therapy for prostate cancer.
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http://dx.doi.org/10.1177/10668969221081740DOI Listing
February 2022

Papillary renal cell carcinoma: a single institutional study of 199 cases addressing classification, clinicopathologic and molecular features, and treatment outcome.

Mod Pathol 2022 06 23;35(6):825-835. Epub 2021 Dec 23.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

The morphologic spectrum of type 1 papillary renal cell carcinoma (PRCC) is not well-defined, since a significant proportion of cases have mixed type 1 and 2 histology. We analyzed 199 cases of PRCC with any (even if focal) type 1 features, with a median follow-up of 12 years, to identify clinicopathological features associated with outcome. Ninety-five tumors (48%) of the cohort contained some type 2 component (median amount: 25%; IQR: 10%, 70%). As a group they showed high rates of progression-free (PFS) and cancer-specific survival (CSS). Tumor size, mitotic rate, lymphovascular invasion, sarcomatoid differentiation, sheet-like architecture, and lack of tumor circumscription were significantly associated with CSS (p ≤ 0.015) on univariate analysis. While predominant WHO/ISUP nucleolar grade was associated with PFS (p = 0.013) and CSS (p = 0.030), the presence of non-predominant (<50%) nucleolar grade did not show association with outcome (p = 0.7). PFS and CSS showed no significant association with the presence or the amount of type 2 morphology. We compared the molecular alterations in paired type 1 and type 2 areas in a subset of 22 cases with mixed type 1 and 2 features and identified 12 recurrently mutated genes including TERT, ARID1A, KDM6A, KMT2D, NFE2L2, MET, APC, and TP53. Among 78 detected somatic mutations, 61 (78%) were shared between the paired type 1 and type 2 areas. Copy number alterations, including chromosome 7 and 17 gains, were similar between type 1 and 2 areas. These findings support that type 2 features in a PRCC with mixed histology represent either morphologic variance or clonal evolution. Our study underscores the notion that PRCC with any classic type 1 regions is best considered as type 1 PRCC and assigned the appropriate WHO/ISUP nucleolar grade. It provides additional evidence that type 2 PRCC as a separate category should be re-assessed and likely needs to be abandoned.
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http://dx.doi.org/10.1038/s41379-021-00990-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9177523PMC
June 2022

Common Diagnostic Challenges and Pitfalls in Genitourinary Organs, With Emphasis on Immunohistochemical and Molecular Updates.

Arch Pathol Lab Med 2021 11;145(11):1387-1404

the Department of Pathology, Northwestern University, Chicago, Illinois (Yang).

Context.—: Lesions in the genitourinary (GU) organs, both benign and malignant, can demonstrate overlapping morphology, and practicing surgical pathologists should be aware of these potential pitfalls and consider a broad differential diagnosis for each specific type of lesion involving the GU organs. The following summary of the contents presented at the 6th Annual Chinese American Pathologists Association (CAPA) Diagnostic Course (October 10-11, 2020), supplemented with relevant literature review, exemplifies the common diagnostic challenges and pitfalls for mass lesions of the GU system of adults, including adrenal gland, with emphasis on immunohistochemical and molecular updates when relevant.

Objective.—: To describe the common mass lesions in the GU system of adults, including adrenal gland, with emphasis on the diagnostic challenges and pitfalls that may arise in the pathologic assessment, and to highlight immunohistochemical workups and emerging molecular findings when relevant.

Data Sources.—: The contents presented at the course and literature search comprise our data sources.

Conclusions.—: The diagnostic challenges and pitfalls that arise in the pathologic assessment of the mass lesions in the GU system of adults, including adrenal gland, are common. We summarize the contents presented at the course, supplemented with relevant literature review, and hope to provide a diagnostic framework to evaluate these lesions in routine clinical practice.
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http://dx.doi.org/10.5858/arpa.2021-0107-RADOI Listing
November 2021

A Not-So-Simple Thyroid Nodule.

JAMA Otolaryngol Head Neck Surg 2021 10;147(10):903-904

Division of Endocrinology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas.

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http://dx.doi.org/10.1001/jamaoto.2021.2155DOI Listing
October 2021

LAG-3 expression on peripheral blood cells identifies patients with poorer outcomes after immune checkpoint blockade.

Sci Transl Med 2021 08;13(608)

Department of Medicine, Memorial Sloan Kettering Cancer Center New York, NY 10065, USA.

Immune checkpoint blocking antibodies are a cornerstone in cancer treatment; however, they benefit only a subset of patients and biomarkers to guide immune checkpoint blockade (ICB) treatment choices are lacking. We designed this study to identify blood-based correlates of clinical outcome in ICB-treated patients. We performed immune profiling of 188 ICB-treated patients with melanoma using multiparametric flow cytometry to characterize immune cells in pretreatment peripheral blood. A supervised statistical learning approach was applied to a discovery cohort to classify phenotypes and determine their association with survival and treatment response. We identified three distinct immune phenotypes (immunotypes), defined in part by the presence of a LAG-3CD8 T cell population. Patients with melanoma with a LAG immunotype had poorer outcomes after ICB with a median survival of 22.2 months compared to 75.8 months for those with the LAG immunotype ( = 0.031). An independent cohort of 94 ICB-treated patients with urothelial carcinoma was used for validation where LAG immunotype was significantly associated with response ( = 0.007), survival ( < 0.001), and progression-free survival ( = 0.004). Multivariate Cox regression and stratified analyses further showed that the LAG immunotype was an independent marker of outcome when compared to known clinical prognostic markers and previously described markers for the clinical activity of ICB, PD-L1, and tumor mutation burden. The pretreatment peripheral blood LAG immunotype detects patients who are less likely to benefit from ICB and suggests a strategy for identifying actionable immune targets for further investigation.
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http://dx.doi.org/10.1126/scitranslmed.abf5107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9254663PMC
August 2021

Retroperitoneal Sclerosing Angiomyolipoma with Long-Term Follow up: A Case Report with Unique Clinicopathologic and Genomic Profile.

Int J Surg Pathol 2022 Feb 9;30(1):86-90. Epub 2021 Jun 9.

University of Texas, Southwestern Medical Center, Dallas, USA.

Sclerosing angiomyolipoma (sAML) is a rare variant of the perivascular epithelioid tumors exhibiting distinct morphology with extensive stromal hyalinization, which makes it challenging to recognize. It often lacks an adipose tissue component and melanocytic markers may be expressed only focally, further posing a diagnostic challenge. Here, we report a case of sAML of the left pararenal retroperitoneum in a 52-year-old woman with 92 months of clinical follow up and discuss the histologic features, immunoprofile, molecular alterations, and differential diagnoses that can aid in the diagnosis of this unique and rare entity.
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http://dx.doi.org/10.1177/10668969211021483DOI Listing
February 2022

68Ga-DOTATATE PET/CT Uptake in Prostate With an Incidental Finding of Prostatic Acinar Adenocarcinoma and Metastatic Neuroendocrine Cancer to the Liver.

Clin Nucl Med 2021 Aug;46(8):e428-e430

From the Departments of Radiology.

Abstract: A 69-year-old man with history of metastatic neuroendocrine tumor presented for initial staging with 68Ga-DOTATE PET/CT. 68Ga-DOTATATE PET/CT showed incidental focal increased DOTATATE uptake in the left apical prostate tissue, which was thought to be of benign etiology. Digital rectal examination later was consistent with a palpable nodule along with elevated prostate-specific antigen of 7.0 ng/mL. MRI of prostate demonstrated a 3.8-cm lesion followed by a targeted biopsy that revealed prostatic acinar adenocarcinoma. Chronic inflammatory cell infiltrates were also noted on biopsy, and this may have been the cause of increased DOTATATE uptake seen on 68Ga-DOTATATE PET/CT study.
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http://dx.doi.org/10.1097/RLU.0000000000003721DOI Listing
August 2021

Serum Small RNA Sequencing and miR-375 Assay Do Not Identify the Presence of Pure Teratoma at Postchemotherapy Retroperitoneal Lymph Node Dissection.

Eur Urol Open Sci 2021 Apr 5;26:83-87. Epub 2021 Mar 5.

Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Existing tumor markers for testicular germ cell tumor (TGCT) cannot detect the presence of pure teratoma. Serum miRNAs have strong performance detecting other subtypes of TGCT. Previous reports suggest high levels of miR-375 expression in teratoma tissue. The purpose of this study was to explore the role of serum miRNA, including miR-375, in detecting the presence of teratoma at postchemotherapy retroperitoneal lymph node dissection (PC-RPLND). We prospectively collected presurgical serum from 40 TGCT patients undergoing PC-RPLND (21 with teratoma at RPLND and 19 with no evidence of disease). We examined the utility of serum miR-375-3p and miR-375-5p by quantitative polymerase chain reaction, and searched for other putative serum miRNAs with small RNA sequencing. The area under the receiver operating characteristic curve (AUC) and univariate analyses were utilized to evaluate test characteristics and predictors of teratoma. Both serum miR-375-3p and miR-375-5p exhibited poor performance (miR-375-3p: 86% sensitivity, 32% specificity, AUC: 0.506; miR-375-5p: 55% sensitivity, 67% specificity, AUC: 0.556). Teratoma at orchiectomy was the only predictor of PC-RPLND teratoma. Small RNA sequencing identified three potentially discriminatory miRNAs, but further validation demonstrated no utility. Our results confirm prior reports that serum miR-375 cannot predict teratoma, and suggest that there may not exist a predictive serum miRNA for teratoma.
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http://dx.doi.org/10.1016/j.euros.2021.02.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121258PMC
April 2021

Rare prostate cancer mimic on multiparametric MRI: Cowper's gland hyperplasia.

Urol Case Rep 2021 Sep 3;38:101675. Epub 2021 Apr 3.

Department of Radiology, University of Texas Southwestern Medical Center, USA.

Multiparametric MRI and targeted biopsies of the prostate have been increasingly utilized in men with elevated PSA. It is important to recognize potential mimics of prostate cancer on MRI and on biopsy specimens. Familiarity with the location, imaging and histological appearance of Cowper's glands will prevent misdiagnosis and help avoid unnecessary biopsies. We present a case of Cowper's gland hyperplasia with a review of its imaging and histopathologic characteristics.
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http://dx.doi.org/10.1016/j.eucr.2021.101675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059050PMC
September 2021

Prospective PI-RADS v2.1 Atypical Benign Prostatic Hyperplasia Nodules With Marked Restricted Diffusion: Detection of Clinically Significant Prostate Cancer on Multiparametric MRI.

AJR Am J Roentgenol 2021 08 2;217(2):395-403. Epub 2020 Sep 2.

Department of Radiology, UT Southwestern Medical Center, Clements Imaging Bldg (NE2.210), 5323 Harry Hines Blvd, Dallas, TX 75390.

On the basis of expert consensus, PI-RADS version 2.1 (v2.1) introduced the transition zone (TZ) atypical benign prostatic hyperplasia (BPH) nodule, defined as a TZ lesion with an incomplete or absent capsule (T2 score, 2). PI-RADS v2.1 also included a revised scoring pathway whereby such nodules, if exhibiting marked restricted diffusion (DWI score, 4-5), are upgraded from overall PI-RADS category 2 to category 3 (2 + 1 TZ lesions). The purpose of this study was to compare the rates of detection of clinically significant prostate cancer (csPCa) in prospectively reported 2 + 1 TZ lesions, as defined by PI-RADS v2.1, and conventional 3 + 0 TZ lesions with targeted biopsy as the reference standard. This retrospective study included men with no known PCa or with treatment-naïve grade group (GG) 1 PCa who underwent 3-T multiparametric MRI of the prostate with prospective reporting by means of PI-RADS v2.1. Patients with at least one PI-RADS category 3 TZ lesion who underwent targeted biopsy formed the final sample. Biopsy results were summarized descriptively for 2 + 1 and 3 + 0 lesions. Generalized estimating equations were used to compare csPCa detection rates between groups. Associations between csPCa in 2 + 1 lesions and patient age, PSA level, prostate volume, PSA density, biopsy history, lesion size, and lesion ADC were tested with Kruskal-Wallis and Fisher exact tests. Among 1238 eligible patients who underwent MRI reported with PI-RADS v2.1, 2 + 1 lesions were reported in 6% ( = 69) and 3 + 0 TZ lesions in 7% ( = 87) of patients. No PCa, GG1 PCa, or csPCa was found in 84% ( = 41), 10% ( = 5), and 6% ( = 3) of 49 patients with 2 + 1 lesions who underwent targeted biopsy. Nor were they found in 74% ( = 45), 15% ( = 9), and 11% ( = 7) of 61 patients with 3 + 0 lesions who underwent targeted biopsy. The csPCa detection rate was not significantly different between 2 + 1 and 3 + 0 lesions ( = .31). All cases of csPCa were GG2, except for one 3 + 0 lesion with a GG3 tumor. No clinical or imaging variable was associated with csPCa in 2 + 1 lesions. The rate of csPCa in atypical BPH nodules with marked restricted diffusion was low (6%) and not significantly different from that of conventional 3 + 0 TZ lesions (11%). The results provide prospective clinical data about the revised TZ scoring criterion and pathway in PI-RADS v2.1 for atypical BPH nodules with marked restricted diffusion.
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http://dx.doi.org/10.2214/AJR.20.24370DOI Listing
August 2021

Real-World Application of Pre-Orchiectomy miR-371a-3p Test in Testicular Germ Cell Tumor Management.

J Urol 2021 Jan 28;205(1):137-144. Epub 2020 Aug 28.

Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas.

Purpose: Current serum tumor markers for testicular germ cell tumor are limited by low sensitivity. Growing evidence supports the use of circulating miR-371a-3p as a superior marker for malignant (viable) germ cell tumor management. We evaluated the real-world application of serum miR-371a-3p levels in detecting viable germ cell tumor among patients undergoing partial or radical orchiectomy.

Materials And Methods: Serum samples were collected from 69 consecutive patients before orchiectomy. Performance characteristics of serum miR-371a-3p were compared with conventional serum tumor markers (⍺-fetoproteinβ-human chorionic gonadotropinlactate dehydrogenase) between patients with viable germ cell tumor and those without viable germ cell tumor on orchiectomy pathology. Relative miR-371a-3p levels were correlated with clinical course. The Kruskal-Wallis test and linear and ordinal regression models were used for analysis.

Results: For detecting viable germ cell tumor, combined conventional serum tumor markers had a specificity of 100%, sensitivity of 58% and AUC of 0.79. The miR-371a-3p test showed a specificity of 100%, sensitivity of 93% and AUC of 0.978. Median relative expression of miR-371a-3p in viable germ cell tumor cases was more than 6,800-fold higher than in those lacking viable germ cell tumor. miR-371a-3p levels correlated with composite stage (p=0.006) and, among composite stage I cases, independently associated with embryonal carcinoma percentage (p=0.0012) and tumor diameter (p <0.0001). Six patients underwent orchiectomy after chemotherapy and were correctly predicted to have presence or absence of viable germ cell tumor by the miR-371a-3p test.

Conclusions: If validated, the miR-371a-3p test can be used in conjunction with conventional serum tumor markers to aid clinical decision making. A positive miR-371a-3p test in patients after preoperative chemotherapy or with solitary testes could potentially guide subsequent orchiectomy or observation.
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http://dx.doi.org/10.1097/JU.0000000000001337DOI Listing
January 2021

Primary Renal Sarcoma With Gene Fusion in an 18-Year-Old Male: A Rare Lesion With a Diagnostic Quandary.

Int J Surg Pathol 2021 Apr 10;29(2):194-197. Epub 2020 Jul 10.

Department of Pathology, 89063UT Southwestern Medical Center, Dallas TX, USA.

Primary renal sarcoma with gene fusion is a rare tumor with only 7 cases reported in the English literature. The morphologic features of this tumor strikingly overlap with clear cell sarcoma of the kidney and synovial sarcoma. Accurate diagnosis can be challenging. In this article, we report a case of an 18-year-old male who presented with hematuria. Subsequent imaging study showed a left renal mass with level II (infra-hepatic) inferior vena cava thrombus, which was resected. Detailed pathologic findings and immunohistochemical and molecular studies revealed an ovoid to spindle cell renal mass with a gene fusion.
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http://dx.doi.org/10.1177/1066896920941087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7800313PMC
April 2021

Distinctive mechanisms underlie the loss of SMARCB1 protein expression in renal medullary carcinoma: morphologic and molecular analysis of 20 cases.

Mod Pathol 2019 09 12;32(9):1329-1343. Epub 2019 Apr 12.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Renal medullary carcinoma is a rare but highly aggressive type of renal cancer occurring in patients with sickle cell trait or rarely with other hemoglobinopathies. Loss of SMARCB1 protein expression, a core subunit of the switch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex, has emerged as a key diagnostic feature of these tumors. However, the molecular mechanism underlying this loss remains unclear. We retrospectively identified 20 patients diagnosed with renal medullary carcinoma at two institutions from 1996 to 2017. All patients were confirmed to have sickle cell trait, and all tumors exhibited a loss of SMARCB1 protein expression by immunohistochemistry. The status of SMARCB1 locus was examined by fluorescence in situ hybridization (FISH) using 3-color probes, and somatic alterations were detected by targeted next-generation sequencing platforms. FISH analysis of all 20 cases revealed 11 (55%) with concurrent hemizygous loss and translocation of SMARCB1, 6 (30%) with homozygous loss of SMARCB1, and 3 (15%) without structural or copy number alterations of SMARCB1 despite protein loss. Targeted sequencing revealed a pathogenic somatic mutation of SMARCB1 in one of these 3 cases that were negative by FISH. Tumors in the 3 subsets with different FISH findings largely exhibited similar clinicopathologic features, however, homozygous SMARCB1 deletion was found to show a significant association with the solid growth pattern, whereas tumors dominated by reticular/cribriform growth were enriched for SMARCB1 translocation. Taken together, we demonstrate that different molecular mechanisms underlie the loss of SMARCB1 expression in renal medullary carcinoma. Biallelic inactivation of SMARCB1 occurs in a large majority of cases either via concurrent hemizygous loss and translocation disrupting SMARCB1 or by homozygous loss.
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http://dx.doi.org/10.1038/s41379-019-0273-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731129PMC
September 2019

Astragaloside IV Inhibits the Progression of Non-Small Cell Lung Cancer Through the Akt/GSK-3β/β-Catenin Pathway.

Oncol Res 2019 Mar 21;27(4):503-508. Epub 2018 Aug 21.

School of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang Province, P.R. China.

Astragaloside IV (AS-IV) is an active ingredient in and is involved in various biological processes, such as regulating the immune system, and counteracting inflammation and malignancy. The aim of this study was to explore the effect of AS-IV on non-small cell lung cancer (NSCLC) cells. Cell counting kit (CCK)-8 assay and flow cytometry were performed to investigate cell survival and cell death, and Western blotting was performed to assess protein expression. We found that AS-IV inhibited the migration and proliferation of NSCLC cells and caused a noticeable increase in cell death. Furthermore, the expression of Bax, a marker of cell death, was increased, whereas the expression of Bcl-2, an antiapoptotic protein, was reduced. AS-IV also promoted cleavage of caspase-3, another indication of apoptosis. Finally, the Akt/GSK-3β/β-catenin axis was suppressed in response to AS-IV. Taken together, these findings provide evidence that AS-IV inhibits NSCLC development via inhibition of the Akt/GSK-3β/β-catenin signaling axis. We therefore propose that AS-IV represents a promising novel agent for the treatment of NSCLC.
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http://dx.doi.org/10.3727/096504018X15344989701565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848426PMC
March 2019

Performance of different prostate specific antibodies in the cytological diagnosis of metastatic prostate adenocarcinoma.

Diagn Cytopathol 2017 Nov 9;45(11):998-1004. Epub 2017 Sep 9.

Case Western Reserve University/University Hospitals Cleveland Medical Center, Cleveland, Ohio 44106.

Background: Diagnosis of metastatic prostate adenocarcinoma (metPA) in cytology specimens can be challenging and frequently requires the use of immunohistochemistry (IHC). Prostate specific membrane antigen (PSMA) and NKX3.1 have emerged as promising IHC markers to determine prostatic origin of metPA in surgical specimens. Our goal is to evaluate the performance of PSMA and NKX3.1 and compare them with those of prostate-specific antigen (PSA) and prostate specific alkaline phosphatase (PSAP) in the cytological diagnosis of metPA MATERIALS: Cytology specimens from patients with a history of prostate adenocarcinoma at our institution between January 01, 2005 and December 31, 2015 were retrieved. IHC stains were performed on the cell blocks. In addition to the staining pattern and intensity, the sensitivity, and specificity of PSMA and NKX3.1 were assessed and compared to those of PSA and PSAP markers.

Results: A total of 56 cytology cases were retrieved with the following diagnoses: 13 metPA, 37 metastatic carcinomas from other origins, 4 rare atypical cells, and 2 benign. Additional 9 cases were re-classified as metPA based on positive PSMA and/or NKX3.1 immunostains. In our cohort of 22 cases of metPA, 18 were positive for PSMA (82%), 15 for NKX3.1 (68%), 9 for PSA (41%), and 9 for PSAP (41%). PSMA and NKX3.1 were negative in all 6 cases of metastatic carcinoma of nonprostate origin (specificity 100%). PSMA demonstrated strong membranous staining pattern, and NKX3.1 exhibited moderate nuclear staining pattern.

Conclusion: Because of their higher sensitivity and specificity, PSMA and NKX3.1 are valuable surrogate markers for metPA in cytology specimens, when compared with PSA and PSAP markers.
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http://dx.doi.org/10.1002/dc.23809DOI Listing
November 2017

Is all inflammation within temporal artery biopsies temporal arteritis?

Hum Pathol 2016 11 18;57:17-21. Epub 2016 Jul 18.

Department of Pathology, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, OH 44106. Electronic address:

Temporal arteritis peaks during the eighth decade, affecting patients with frequent comorbidities who are especially prone to adverse effects of corticosteroid therapy. Perivascular inflammation involving small periadventitial vessels is not uncommon in otherwise normal temporal artery biopsies (TABs). As ischemic events occur in patients with non-temporal artery--based inflammation, it has been recommended that any vascular inflammation within TABs be treated with corticosteroids. We sought to determine whether such patients are at increased risk for temporal arteritis-like adverse events compared with age-matched controls devoid of inflammatory infiltrates. TABs without transmural temporal arteritic damage accessioned between 2002 and 2012 were reviewed for inflammation (>15 perivascular lymphocytes) involving small blood vessels and/or temporal artery adventitia. Of 343 TABs, 278 (81%) were negative for transmural arteritis. Inflammation involving small vessels and/or temporal artery adventitia was present in 56 cases (20%). Age-matched controls were available for 39 cases. With a mean follow-up of 5 years (range, 1-11 years), 6/39 (15%) of patients developed stroke or cardiovascular events or died compared with 7/39 (18%) of age-matched controls. None of the patients with study-positive TAB had documented steroid therapy before or after TAB. Our results demonstrate that patients with inflammation involving only small vessels or temporal artery adventitia are not at increased risk for temporal arteritis-like adverse events, and suggest that the risks of protracted corticosteroid therapy in this elderly population likely exceed any potential benefits. We advise against diagnosing vasculitis in the absence of temporal arteritic damage.
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http://dx.doi.org/10.1016/j.humpath.2016.07.004DOI Listing
November 2016

1,2-Bis[(3,6,9-trimethyl-3,12-ep-oxy-3,4,5,5a,6,7,8,8a,9,10,12,12a-dodeca-hydro-pyrano[4,3-j][1,2]benzodioxepin-4-yl)-oxy]ethane.

Acta Crystallogr Sect E Struct Rep Online 2012 Mar 10;68(Pt 3):o661. Epub 2012 Feb 10.

The title compound, C(32)H(50)O(10), prepared from a mixture of α- and β-dihydro-artemisinin, has two β-arteether moieties linked via an -OCH(2)CH(2)O- bridge, so that the mol-ecule is symmetric about the bridge. Each asymmetric unit contains a β-arteether moiety and an -OCH(2) group, which is only one-half of the mol-ecule. The endo-peroxide bridges of the parent compounds have been retained in each half of the diol-bridged dimer. The rings exhibit chair and twist-boat conformations.
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http://dx.doi.org/10.1107/S1600536812005089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3295452PMC
March 2012

Distinct roles of cadherin-6 and E-cadherin in tubulogenesis and lumen formation.

Mol Biol Cell 2011 Jun 20;22(12):2031-41. Epub 2011 Apr 20.

Department of Surgery, Committee on Cancer Biology, University of Chicago, IL 60637, USA.

Classic cadherins are important regulators of tissue morphogenesis. The predominant cadherin in epithelial cells, E-cadherin, has been extensively studied because of its critical role in normal epithelial development and carcinogenesis. Epithelial cells may also coexpress other cadherins, but their roles are less clear. The Madin Darby canine kidney (MDCK) cell line has been a popular mammalian model to investigate the role of E-cadherin in epithelial polarization and tubulogenesis. However, MDCK cells also express relatively high levels of cadherin-6, and it is unclear whether the functions of this cadherin are redundant to those of E-cadherin. We investigate the specific roles of both cadherins using a knockdown approach. Although we find that both cadherins are able to form adherens junctions at the basolateral surface, we show that they have specific and mutually exclusive roles in epithelial morphogenesis. Specifically, we find that cadherin-6 functions as an inhibitor of tubulogenesis, whereas E-cadherin is required for lumen formation. Ablation of cadherin-6 leads to the spontaneous formation of tubules, which depends on increased phosphoinositide 3-kinase (PI3K) activity. In contrast, loss of E-cadherin inhibits lumen formation by a mechanism independent of PI3K.
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http://dx.doi.org/10.1091/mbc.E11-01-0038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3113768PMC
June 2011

Cadherins and Pak1 control contact inhibition of proliferation by Pak1-betaPIX-GIT complex-dependent regulation of cell-matrix signaling.

Mol Cell Biol 2010 Apr 12;30(8):1971-83. Epub 2010 Feb 12.

Department of Surgery, University of Chicago, Chicago, IL 60637, USA.

It is crucial for organ homeostasis that epithelia have effective mechanisms to restrict motility and cell proliferation in order to maintain tissue architecture. On the other hand, epithelial cells need to rapidly and transiently acquire a more mesenchymal phenotype, with high levels of cell motility and proliferation, in order to repair epithelia upon injury. Cross talk between cell-cell and cell-matrix signaling is crucial for regulating these transitions. The Pak1-betaPIX-GIT complex is an effector complex downstream of the small GTPase Rac1. We previously showed that translocation of this complex from cell-matrix to cell-cell adhesion sites was required for the establishment of contact inhibition of proliferation. In this study, we provide evidence that this translocation depends on cadherin function. Cadherins do not recruit the complex by direct interaction. Rather, we found that inhibition of the normal function of cadherin or Pak1 leads to defects in focal adhesion turnover and to increased signaling by phosphatidylinositol 3-kinase. We propose that cadherins are involved in regulation of contact inhibition by controlling the function of the Pak1-betaPIX-GIT complex at focal contacts.
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http://dx.doi.org/10.1128/MCB.01247-09DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2849475PMC
April 2010

Effects of Wnt proteins on cell proliferation and apoptosis in HEK293 cells.

Cell Biol Int 2008 Jul 29;32(7):807-13. Epub 2008 Mar 29.

State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Datun Road, Chaoyang District, Beijing 100101, PR China.

Wnt proteins and Wnt signalings have been implicated in a variety of development and cell processes, while aberrant activation of Wnt signaling is linked to a range of cancers in many tissues. In this study, we used the HEK293 cell line to investigate the effects of Wnt3a and Wnt5a on proliferation and apoptosis in a serum starvation culture. After Wnt3a and Wnt5a proteins were expressed, they both promoted the proliferation of HEK293 cells under serum starvation. After 48h of serum starvation, both Wnt3a and Wnt5a inhibited serum starvation-induced apoptosis of HEK293 cells and continued up to 96h. We demonstrated that Wnt3a and Wnt5a can promote proliferation of HEK293 cells and inhibit serum starvation-induced apoptosis, which implies that Wnt3a and Wnt5a can maintain the survival of HEK293 cells under stress, and also provide a novel insight into the role of Wnt3a and Wnt5a and their related signalings in carcinogenesis.
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http://dx.doi.org/10.1016/j.cellbi.2008.03.011DOI Listing
July 2008

Dickkopf-1 secreted by decidual cells promotes trophoblast cell invasion during murine placentation.

Reproduction 2008 Mar;135(3):367-75

State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Datun Road, Chaoyang District, Beijing 100101, China.

Dickkopf-1 (Dkk1) is one of the secreted antagonists in the canonical Wnt signaling pathway. It plays important roles in diverse developmental processes. However, the role of Dkk1 in trophoblast cell invasion during placentation remains unclear. In this study, we found that Dkk1 was mainly expressed in maternal decidual tissue but trivially in ectoplacental cones (EPCs) in day 8 post coitum (p.c.) pregnant mouse uterus and that the efficiency of EPC attachment and outgrowth was increased when co-cultured with decidual cells, which secreted Dkk1, and this enhancement was abolished by pretreating decidual cells with Dkk1 blocking antibody before co-culture experiment. This indicates that Dkk1 secreted by decidual cells plays an important role in trophoblast cell invasion. Indeed, when recombinant mouse Dkk1 was added to EPCs in vitro, the efficiency of attachment and outgrowth was increased. Migration of EPCs toward the decidua was retarded when antisense Dkk1 oligonucleotide (ODN) was administered via intrauterine injection in vivo. Furthermore, the active beta-catenin nuclear location was lost when we treated cultured EPCs with recombinant mouse Dkk1, and the efficiency of EPCs attachment and outgrowth was obviously increased when we treated cultured EPCs with antisense beta-catenin ODN. Taken together, Dkk1 secreted by decidual cells may induce trophoblast cell invasion in the mouse and beta-catenin may be involved in such functions of Dkk1.
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http://dx.doi.org/10.1530/REP-07-0191DOI Listing
March 2008

Effects of Wnt3a on proliferation and differentiation of human epidermal stem cells.

Biochem Biophys Res Commun 2008 Apr 31;368(3):483-8. Epub 2008 Jan 31.

State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Datun Road, Chaoyang District, Beijing 100101, People's Republic of China.

Epidermal stem cells maintain development and homeostasis of mammalian epidermis throughout life. However, the molecular mechanisms involved in the proliferation and differentiation of epidermal stem cells are far from clear. In this study, we investigated the effects of Wnt3a and Wnt/beta-catenin signaling on proliferation and differentiation of human fetal epidermal stem cells. We found both Wnt3a and active beta-catenin, two key members of the Wnt/beta-catenin signaling, were expressed in human fetal epidermis and epidermal stem cells. In addition, Wnt3a protein can promote proliferation and inhibit differentiation of epidermal stem cells in vitro culture. Our results suggest that Wnt/beta-catenin signaling plays important roles in human fetal skin development and homeostasis, which also provide new insights on the molecular mechanisms of oncogenesis in human epidermis.
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http://dx.doi.org/10.1016/j.bbrc.2008.01.097DOI Listing
April 2008

Enrichment of putative human epidermal stem cells based on cell size and collagen type IV adhesiveness.

Cell Res 2008 Mar;18(3):360-71

State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Datun Road, Chaoyang District, Beijing 100101, China.

The enrichment and identification of human epidermal stem cells (EpSCs) are of paramount importance for both basic research and clinical application. Although several approaches for the enrichment of EpSCs have been established, enriching a pure population of viable EpSCs is still a challenging task. An improved approach is worth developing to enhance the purity and viability of EpSCs. Here we report that cell size combined with collagen type IV adhesiveness can be used in an improved approach to enrich pure and viable human EpSCs. We separated the rapidly adherent keratinocytes into three populations that range in size from 5-7 microm (population A), to 7-9 microm (population B), to > or =9 microm (population C) in diameter, and found that human putative EpSCs could be further enriched in population A with the smallest size. Among the three populations, population A displayed the highest density of beta1-integrin receptor, contained the highest percentage of cells in G0/G1 phase, showed the highest nucleus to cytoplasm ratio, and possessed the highest colony formation efficiency (CFE). When injected into murine blastocysts, these cells participated in multi-tissue formation. More significantly, compared with a previous approach that sorted putative EpSCs according to beta1-integrin antibody staining, the viability of the EpSCs enriched by the improved approach was significantly enhanced. Our results provide a putative strategy for the enrichment of human EpSCs, and encourage further study into the role of cell size in stem cell biology.
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http://dx.doi.org/10.1038/cr.2007.103DOI Listing
March 2008
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