Frank McKeon

National University Health System, Singapore

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Publications (116)1539.37 Total impact

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    ABSTRACT: Lung diseases such as chronic obstructive pulmonary disease and pulmonary fibrosis involve the progressive and inexorable destruction of oxygen exchange surfaces and airways, and have emerged as a leading cause of death worldwide. Mitigating therapies, aside from impractical organ transplantation, remain limited and the possibility of regenerative medicine has lacked empirical support. However, it is clinically known that patients who survive sudden, massive loss of lung tissue from necrotizing pneumonia or acute respiratory distress syndrome often recover full pulmonary function within six months. Correspondingly, we recently demonstrated lung regeneration in mice following H1N1 influenza virus infection, and linked distal airway stem cells expressing Trp63 (p63) and keratin 5, called DASC(p63/Krt5), to this process. Here we show that pre-existing, intrinsically committed DASC(p63/Krt5) undergo a proliferative expansion in response to influenza-induced lung damage, and assemble into nascent alveoli at sites of interstitial lung inflammation. We also show that the selective ablation of DASC(p63/Krt5) in vivo prevents this regeneration, leading to pre-fibrotic lesions and deficient oxygen exchange. Finally, we demonstrate that single DASC(p63/Krt5)-derived pedigrees differentiate to type I and type II pneumocytes as well as bronchiolar secretory cells following transplantation to infected lung and also minimize the structural consequences of endogenous stem cell loss on this process. The ability to propagate these cells in culture while maintaining their intrinsic lineage commitment suggests their potential in stem cell-based therapies for acute and chronic lung diseases.
    Nature 11/2014; · 38.60 Impact Factor
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    ABSTRACT: The oviducts contain high grade serous cancer (HGSC) precursors (serous tubal intraepithelial neoplasia or STINs), which are γ-H2AXp- and TP53 mutation-positive. Although they express wild type p53, secretory cell outgrowths (SCOUTs) are associated with older age and serous cancer; moreover both STINs and SCOUTs share a loss of PAX2 expression (PAX2n). We evaluated PAX2 expression in proliferating adult and embryonic oviductal cells, normal mucosa, SCOUTs, Walthard cell nests (WCNs), STINs and HGSCs, and the expression of genes chosen empirically or from SCOUT expression arrays. Clones generated in vitro from embryonic gynecologic tract and adult fallopian tube were Krt7p/ PAX2n/EZH2p and underwent ciliated (PAX2n/EZH2n/FOXJ1p) and basal (Krt7n/EZH2n/Krt5p) differentiation. Similarly non-ciliated cells in normal mucosa were PAX2p but became PAX2n in multilayered epithelium undergoing ciliated or basal (Walthard cell nests or WCN) cell differentiation. PAX2n SCOUTs fell into two groups; Type I were secretory or secretory/ciliated with a “tubal” phenotype and were ALDH1n and β-cateninmem (membraneous only). Type II displayed a columnar to pseudostratified (endometrioid) phenotype, with an EZH2p, ALDH1p, β-cateninnc (nuclear and cytoplasmic), stathminp, LEF1p, RCN1p and RUNX2p expression signature. STINs and HGSCs shared the Type I immunophenotype of PAX2n, ALDH1n, β-cateninmem, but highly expressed EZH2p, LEF1p, RCN1p, and stathminp. This study, for the first time, links PAX2n with proliferating fetal and adult oviductal cells undergoing basal and ciliated differentiation and shows that this expression state is maintained in SCOUTs, STINs and HGSCs. All three entities can demonstrate a consistent perturbation of genes involved in potential tumor suppressor gene silencing (EZH2), transcriptional regulation (LEF1), regulation of differentiation (RUNX2), calcium binding (RCN1) and oncogenesis (stathmin). This shared expression signature between benign and neoplastic entities links normal progenitor cell expansion to abnormal and neoplastic outgrowth in the oviduct and exposes a common pathway that could be a target for early prevention.
    The Journal of Pathology 08/2014; · 7.59 Impact Factor
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    ABSTRACT: Barrett's oesophagus is a premalignant condition, predisposing to oesophageal adenocarcinoma. However, some adenocarcinoma may arise in columnar lined oesophagus without goblet cells. Our aim was to evaluate the biological properties of non-goblet columnar lined oesophagus only and elucidate its relationship with Barrett's oesophagus and associated neoplasia. Endoscopic biopsies from patients with Barrett's oesophagus (n=30), non-goblet columnar lined oesophagus (n=14), Barrett's oesophagus associated high grade dysplasia (n=6) and adenocarcinoma (n=4) were selected. Immunostaining for villin, claudin 3 and MUC4 was performed. Statistical analysis was performed and a p value <0.05 was considered significant. Villin and MUC4 were positive in 42%, 100% each and 50% in non-goblet columnar lined oesophagus, Barrett's oesophagus, high grade dysplasia and adenocarcinoma respectively, while claudin 3 was 100% positive in all the groups. In non-goblet columnar lined oesophagus, six cases that were villin immunopositive, showed positive expression for claudin 3 and/or MUC4 and there was no difference from the high grade dysplasia or adenocarcinoma (p>0.05). Our results indicate that a subset of non-goblet columnar lined oesophagus shows an intestinal phenotype representing an early stage of Barrett's oesophagus. This subset probably harbours the potential to change into adenocarcinoma in the long term.
    Digestive and Liver Disease 11/2013; · 3.16 Impact Factor
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    ABSTRACT: Squamous cell carcinoma (SCC) is highly malignant and refractory to therapy. The majority of existing mouse SCC models involve multiple gene mutations. Very few mouse models of spontaneous SCC have been generated by a single gene deletion. Here we report a haploinsufficient SCC mouse model in which exon 3 of the Tp53BP2 gene (a p53 binding protein) was deleted in one allele in a BALB/c genetic background. Tp53BP2 encodes ASPP2 (ankyrin repeats, SH3 domain and protein rich region containing protein 2). Keratinocyte differentiation induces ASPP2 and its expression is inversely correlated with p63 protein in vitro and in vivo. Up-regulation of p63 expression is required for ASPP2(Δexon3/+) BALB/c mice to develop SCC, as heterozygosity of p63 but not p53 prevents them from developing it. Mechanistically, ASPP2 inhibits ΔNp63 expression through its ability to bind IκB and enhance nuclear Rel/A p65, a component of the NF-κB transcription complex, which mediates the repression of p63. Reduced ASPP2 expression associates with tumor metastasis and increased p63 expression in human head and neck SCCs. This study identifies ASPP2 as a tumor suppressor that suppresses SCC via inflammatory signaling through NF-κB-mediated repression of p63.
    Proceedings of the National Academy of Sciences 10/2013; · 9.81 Impact Factor
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    ABSTRACT: It is currently hoped that deaths from extra-uterine high-grade serous cancer (HGSC) will be reduced via opportunistic salpingectomy in healthy women. Accumulated data implicate the fimbria as a site of origin and descriptive molecular pathology and experimental evidence strongly support a serous carcinogenic sequence in the fallopian tube. Both direct and indirect ("surrogate") precursors suggest the benign tube undergoes important biologic changes after menopause, acquiring abnormalities in gene expression that are often shared with malignancy, including PAX2, ALDH1, LEF1, RCN1, RUNX2, beta catenin, EZH2 and others. However, the tube can be linked to only some HGSCs, recharging arguments that nearby peritoneum/ovarian surface epithelium (POSE) also hosts progenitors to this malignancy. A major sticking point is the difference in immunophenotype between POSE and Müllerian epithelium, essentially requiring mesothelial to Müllerian differentiation prior to or during malignant transformation to HGSC. However, emerging evidence implicates an embryonic or progenitor phenotype in the adult female genital tract with the capacity to differentiate, normally or during neoplastic transformation. Recently, a putative cell of origin to cervical cancer has been identified in the squamo-columnar (SC) junction, projecting a model whereby Krt7+ embryonic progenitors give rise to immuno-phenotypically distinct progeny under stromal influences via "top down" differentiation. Similarly, biphasic cell differentiation can be seen in the endometrium with a parallel in the juxtaposition of mesothelial and mullerian differentiation in the ovary. An abrupt mesothelial-Mullerian transition remains to be proven, but would explain the rapid evolution, short asymptomatic interval, and absence of a defined epithelial starting point in many HGSCs. Resolving this question will require accurately distinguishing progenitor from progeny tumor cells in HGSC and pinpointing where initial transformation and trans-differentiation occurs if the POSE is an origin. Both will be critical to expectations from prophylactic salpingectomy and future approaches to pelvic serous cancer prevention.
    The Journal of Pathology 09/2013; · 7.59 Impact Factor
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    ABSTRACT: Low-grade cervical squamous abnormalities (low-grade squamous intraepithelial lesions [LSIL, CIN1]) can be confused with or followed by high-grade (HSIL, CIN2/3) lesions, expending considerable resources. Recently, a cell of origin for cervical neoplasia was proposed in the squamocolumnar junction (SCJ); HSILs are almost always SCJ, but LSILs include SCJ and SCJ subsets. Abnormal cervical biopsies from 214 patients were classified by 2 experienced pathologists (panel) as LSIL or HSIL using published criteria. SILs were scored SCJ and SCJ using SCJ-specific antibodies (keratin7, AGR2, MMP7, and GDA). Assessments of interobserver agreement, p16 staining pattern, proliferative index, and outcome were compared. The original diagnostician agreed with the panel diagnosis of HSIL and SCJ LSIL in all cases (100%). However, for SCJ LSIL, panelists disagreed with each other by 15% and with the original diagnostician by 46.2%. Comparing SCJ and SCJ LSILs, 60.2% and 94.9% were p16 positive, 23% and 74.4% showed strong (full-thickness) p16 staining, and 0/54 (0%) and 8/33 (24.2%) with follow-up had an HSIL outcome, respectively. Some SCJ LSILs are more likely to both generate diagnostic disagreement and be associated with HSIL. Conversely, SCJ LSILs generate little observer disagreement and, when followed, have a very low risk of HSIL outcome. Thus, SCJ biomarkers in conjunction with histology may segregate LSILs with very low risk of HSIL outcome and conceivably could be used as a management tool to reduce excess allocation of resources to the follow-up of these lesions.
    The American journal of surgical pathology 09/2013; 37(9):1311-8. · 4.06 Impact Factor
  • Wa Xian, Frank McKeon, Khek Yu Ho
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    ABSTRACT: The best means to improve gastrointestinal cancer survival is screening and treatment of the early lesions. In esophageal adenocarcinoma, there is increasing thought that low-grade dysplasia and perhaps even "high-risk" Barrett's esophagus represent the most attractive targets for achieving a cure. An issue with Barrett's esophagus is that endoscopy alone cannot distinguish Barrett's esophagus from columnar lined epithelium or from areas of low-grade dysplasia. Much effort has therefore been devoted to discover molecular biomarkers of "high-risk" states and develop imaging tools for detecting these biomarkers in a manner that could assist the real-time in-vivo targeting of sites for biopsy. The strategy we have employed is to generate stem cell clones from Barrett's esophagus biopsies and compare their gene expression profiles with patient-matched stem cell clones of the esophageal squamous epithelia and gastric cardia. It is anticipated that by mining the expression datasets of these Barrett's stem cell clones, we will be able to identify unique cell surface markers of the Barrett's stem cells against which cytotoxic antibodies or aptamers can be developed, and used to aid the endoscopist in identifying regions of atypia for biopsy, making real-time diagnosis, stratifying patients during the examination, and ultimately directing therapy in a preemptive manner. This review will focus on Barrett's esophagus and its associated neoplasia to illustrate the utility of biomarker and molecular imaging in aiding targeted biopsy, making real-time diagnosis, stratifying lesions during examination, and directing treatment of this gastrointestinal disorder during surveillance endoscopy.
    Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 08/2013; · 5.64 Impact Factor
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    ABSTRACT: Serous tubal intraepithelial carcinoma (STIC) is a noninvasive phase of pelvic serous cancer at risk for metastasizing. Because of its biologic significance, its accurate distinction from nonmalignant mimics is important. Loss of cell orientation is an important feature of STIC. We sought to determine whether the immunohistochemical localization of cytoskeletal-organizing proteins phospho-ezrin-radaxin-moesin (p-ERM) would be useful in making this distinction. The benign oviductal entities (normal and p53 signatures), premalignant atypias (tubal intraepithelial lesions in transition), serous intraepithelial carcinomas (STICs), and carcinomas were analyzed for 5 staining patterns and compared. Linear or uniform luminal p-ERM staining was strongly associated with benign mucosa in contrast to STICs, in which it was lost and often replaced by nonlinear or nonuniform patterns highlighting individually cell groups or single cells. Premalignant atypias were similar to benign mucosa by p-ERM staining and retained the linear luminal pattern. This study shows, for the first time, that patterns of staining for an immunohistochemical correlate of cell polarity (p-ERM) differ between STICs, their benign counterparts and premalignant atypias that do not fulfill the criteria for STICs. If confirmed, these findings warrant further analysis of indices of cell polarity as objective markers for the diagnosis and mapping of the evolution of pelvic serous precursors.
    International journal of gynecological pathology: official journal of the International Society of Gynecological Pathologists 05/2013; · 2.07 Impact Factor
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    ABSTRACT: The cervical squamocolumnar (SC) junction is the site of a recently discovered "embryonic" cell population that was proposed as the cell of origin for cervical cancer and its precursors. How this population participates in cervical remodeling and neoplasia is unclear. In the present study, we analyzed the SC junction immunophenotype during pre and postnatal human and mouse development and in the adult, processes of metaplastic evolution of SC junction, microglandular change and early cervical neoplasia. Early in life, embryonic cervical epithelial cells were seen throughout the cervix and subsequently diminished in number to become concentrated at the SC junction in the adult. In all settings, there was a repetitive scenario in which cuboidal embryonic/SC junction cells gave rise to subjacent metaplastic basal/reserve cells with a switch from the SC junction positive to negative immunophenotype. This downward or basal (rather than upward or apical) evolution from progenitor cell to metaplastic progeny was termed reverse or "top down" differentiation. A similar pattern was noted in high grade squamous intraepithelial lesions (HSIL), suggesting HPV infection of the cuboidal SC junction cells initiated outgrowth of basally-oriented neoplastic progeny. The progressive loss of the embryonic/SC junction markers occurred with top-down differentiation during development, remodeling and early neoplasia. Interestingly, most low grade SILs were SC junction negative, implying infection of metaplastic progeny rather than the original SC junction cells. This proposed model of "top down" differentiation resolves the mystery of how SC junction cells both remodel the cervix and participate in neoplasia and provides for a second population of metaplastic progeny (including basal and reserve cells), the infection of which is paradoxically less likely to produce a biologically aggressive precursor. It also provides new targets in animal models to determine why the SC junction is uniquely susceptible to carcinogenic HPV infection. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
    The Journal of Pathology 09/2012; · 7.59 Impact Factor
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    ABSTRACT: Previous efforts to derive lung progenitor cells from human embryonic stem (hES) cells using embryoid body formation or stromal feeder cocultures had been limited by low efficiencies. Here, we report a step-wise differentiation method to drive both hES and induced pluripotent stem (iPS) cells toward the lung lineage. Our data demonstrated a 30% efficiency in generating lung epithelial cells (LECs) that expresses various distal lung markers. Further enrichment of lung progenitor cells using a stem cell marker, CD166 before transplantation into bleomycin-injured NOD/SCID mice resulted in enhanced survivability of mice and improved lung pulmonary functions. Immunohistochemistry of lung sections from surviving mice further confirmed the specific engraftment of transplanted cells in the damaged lung. These cells were shown to express surfactant protein C, a specific marker for distal lung progenitor in the alveoli. Our study has therefore demonstrated the proof-of-concept of using iPS cells for the repair of acute lung injury, demonstrating the potential usefulness of using patient's own iPS cells to prevent immune rejection which arise from allogenic transplantation.Molecular Therapy (2012); doi:10.1038/mt.2012.182.
    Molecular Therapy 09/2012; · 7.04 Impact Factor
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    ABSTRACT: A high frequency of precursor lesions is a risk factor for cancer in many organ systems but must be precisely quantified. Pelvic serous neoplasia is associated with an estimated increase in frequency of secretory cell outgrowths (SCOUTs) with loss of PAX2 protein (PAX2p) expression (PAX2p-null SCOUTs) in the fallopian tube. However, to confirm this, PAX2p-null SCOUTs must be precisely quantified relative to the epithelial surface. We developed a method by which fallopian tube sections were digitized using an iScan brightfield scanner (BioImagene) and uploaded in Adobe Photoshop CS3 Extended. Pixel length was translated into microns and epithelial length measured with the Magic Wand tool. SCOUTs were expressed as a function of total epithelial perimeter. Frequency, required perimeter length, topographic clustering tendency and effects of age were ascertained. SCOUT frequency per 10 cm was 0-4.60 for cases and 0-1.66 for controls, averaging 0.84 and 0.27, respectively, (P=0.007). Required perimeter length for SCOUT detection was less in serous cancer cases and topographic distribution followed a random pattern without aberrant clustering. Age was also associated with SCOUT frequency (P=0.025) and differences between cancers and controls were still significant after adjusting for age (P=0.001). We describe an efficient method for quantifying epithelial perimeter in the fallopian tube and verify its relevance to precursor frequency. This has important implications for assessing precursor frequency both in the fallopian tube and in other organs-such as prostate, pancreas and colon-where epithelial precursors are integral to carcinogenesis.Modern Pathology advance online publication, 6 July 2012; doi:10.1038/modpathol.2012.100.
    Modern Pathology 07/2012; · 5.25 Impact Factor
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    ABSTRACT: Infection by carcinogenic human papillomaviruses (HPV) results in precancers [cervical intraepithelial neoplasia (CIN)] and cancers near the ectoendocervical squamocolumnar (SC) junction of the cervix. However, the specific cells targeted by HPV have not been identified and the cellular origin of cervical cancer remains elusive. In this study, we uncovered a discrete population of SC junctional cells with unique morphology and gene-expression profile. We also demonstrated that the selected junctional biomarkers were expressed by a high percentage of high-grade CIN and cervical cancers associated with carcinogenic HPVs but rarely in ectocervical/transformation zone CINs or those associated with noncarcinogenic HPVs. That the original SC junction immunophenotype was not regenerated at new SC junctions following excision, not induced by expression of viral oncoproteins in foreskin keratinocytes, and not seen in HPV-related precursors of the vagina, vulva, and penis further support the notion that junctional cells are the source of cervical cancer. Taken together, our findings suggest that carcinogenic HPV-related CINs and cervical cancers are linked to a small, discrete cell population that localizes to the SC junction of the cervix, expresses a unique gene expression signature, and is not regenerated after excision. The findings in this study uncover a potential target for cervical cancer prevention, provide insight into the risk assessment of cervical lesions, and establish a model for elucidating the pathway to cervical cancer following carcinogenic HPV infection.
    Proceedings of the National Academy of Sciences 06/2012; 109(26):10516-21. · 9.81 Impact Factor
  • Christopher P Crum, Frank D McKeon, Wa Xian
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    ABSTRACT: In recent years, the distal oviduct has emerged as a critical organ in the pathogenesis of pelvic ("ovarian") serous cancer. Studies have uncovered early serous tubal intraepithelial carcinomas in approximately 8% of asymptomatic women with germline BRCA1 or BRCA2 mutations, linked serous tubal intraepithelial carcinomas to one half of serous cancers irrespective of genetic risk, and described a precursor lesion in the distal tube with early alterations in p53 function (the p53 signature). This work has established a linear serous carcinogenic sequence in a single focus within the fimbria. In addition, a more broadly distributed array of gene alterations has been discovered in the oviduct, manifested as secretory (or stem) cell outgrowths that are increased in frequency as a function of older age and serous cancer status. These "surrogate precursors" expand the existing model beyond the fimbria, implying that the molecular events leading to serous cancer are distributed over space and time. The potential promise of these discoveries is "targeted prevention" by discovering of multiple pathways integral to carcinogenesis and successfully preventing malignancy by interrupting one or a few of these pathways.
    International Journal of Gynecological Cancer 05/2012; 22 Suppl 1:S29-34. · 1.94 Impact Factor
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    ABSTRACT: Esophageal adenocarcinoma is on the rise in the West and yet its marginal survival rate has not changed in 30 years. Preemptive approaches, including radiofrequency ablation and photodynamic therapy for Barrett's esophagus and dysplasia, are achieving dramatic initial results. While the long-term efficacy of these non-specific ablative therapies is awaiting longitudinal studies, reports of recurrences are increasing. More targeted therapies, particularly directed at the stem cells of Barrett's esophagus, demand knowing the origin of this intestinal metaplasia. The prevailing concept holds that Barrett's esophagus arises from the "transcommitment" of esophageal stem cells to produce an intestine-like epithelium. Given the remarkable frequency with which Barrett's esophagus appears in Western populations, empirical data for such a transcommitment phenomenon have been surprisingly limited. An alternative explanation derives from the discovery of a discrete population of residual embryonic cells (RECs) existing at the gastroesophageal junction in normal individuals that expands and colonizes regions of the esophagus denuded by chronic reflux. These RECs form intestinal metaplasia within days of esophageal injury, suggesting a novel mechanism of tumorigenesis. A corollary of this work is that the Barrett's stem cell is distinct from that of the squamous epithelium and, once identified, will form the basis of new strategies for addressing Barrett's and its related neoplasia.
    Gastroenterology 04/2012; 142(7):1424-30. · 12.82 Impact Factor
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    ABSTRACT: Acute graft-versus-host disease (GVHD), a major complication of allogeneic stem cell transplantation, involves cytotoxic soluble and cellular effectors that selectively induce apoptosis in normally apoptosis-resistant, cytokeratin 15 (K15)-expressing epithelial stem cells residing at the tips of rete ridges of human epidermis and in analogous rete-like prominences (RLPs) of murine dorsal lingual epithelium. The mechanisms whereby epithelial stem cells are rendered vulnerable to apoptosis during allostimulation are unknown. We hypothesized that GVHD-induced target cell injury may be related to pathways involving the p53 family that are constitutively expressed by epithelial stem cells and designed to trigger physiological apoptosis as a result of environmental danger signals. Among the p53 family members, we found that p73 protein and mRNA were preferentially expressed in K15(+) RLPs of murine lingual squamous epithelium. On in vitro exposure to recombinant TNF-α and IL-1 in an organ culture model previously shown to replicate early GVHD-like target cell injury, apoptosis was selectively induced in K15(+) stem cell regions and was associated with induction of phosphorylated p73, a marker for p73 activation, and apoptosis was abrogated in target tissue obtained from p73-deficient (p73(-/-)) mice. Evaluation of early in vivo lesions in experimental murine GVHD disclosed identical patterns of phosphorylated p73 expression that coincided with the onset of effector T cell infiltration and target cell apoptosis within K15(+) RLPs. This study is the first to suggest that paradoxical apoptosis in GVHD of physiologically protected K15(+) epithelial stem cells is explainable, at least in part, by cytokine-induced activation of suicide pathways designed to eliminate stem cells after exposure to deleterious factors perceived to be harmful to the host.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 03/2012; 18(6):841-51. · 3.15 Impact Factor
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    Wa Xian, Frank McKeon
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    ABSTRACT: Despite the massive toll in human suffering imparted by degenerative lung disease, including COPD, idiopathic pulmonary fibrosis and ARDS, the scientific community has been surprisingly agnostic regarding the potential of lung tissue, and in particular the alveoli, to regenerate. However, there is circumstantial evidence in humans and direct evidence in mice that ARDS triggers robust regeneration of lung tissue rather than irreversible fibrosis. The stem cells responsible for this remarkable regenerative process has garnered tremendous attention, most recently yielding a defined set of cloned human airway stem cells marked by p63 expression but with distinct commitment to differentiated cell types typical of the upper or lower airways, the latter of which include alveoli-like structures in vitro and in vivo. These recent advances in lung regeneration and distal airway stem cells and the potential of associated soluble factors in regeneration must be harnessed for therapeutic options in chronic lung disease.
    Cell cycle (Georgetown, Tex.) 03/2012; 11(5):887-94. · 5.24 Impact Factor
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    Christopher P Crum, Frank D McKeon, Wa Xian
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    ABSTRACT: A novel origin for pelvic serous cancer (ovarian cancer) has been proposed in the distal oviduct. This has important implications, including both early detection in high-risk women and wisdom of relying on serological tests to detect a disease that begins so close to the peritoneal surfaces. With the recent discovery of premalignant disturbances in gene function in the tubal mucosa, the concept of targeted prevention is emerging whereby the interruption of a portion of the carcinogenic pathway will prevent cancer. This alternative to detect early malignancy is a new paradigm in the quest to prevent this deadly disease.
    Clinical obstetrics and gynecology 03/2012; 55(1):24-35. · 2.06 Impact Factor
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    ABSTRACT: The p53-family member TAp73 is a transcription factor that plays a key role in many biological processes. Here, we show that p73 drives the expression of microRNA (miR)-34a, but not miR-34b and -c, by acting on specific binding sites on the miR-34a promoter. Expression of miR-34a is modulated in parallel with that of TAp73 during in vitro differentiation of neuroblastoma cells and cortical neurons. Retinoid-driven neuroblastoma differentiation is inhibited by knockdown of either p73 or miR-34a. Transcript expression of miR-34a is significantly reduced in vivo both in the cortex and hippocampus of p73(-/-) mice; miR-34a and TAp73 expression also increase during postnatal development of the brain and cerebellum when synaptogenesis occurs. Accordingly, overexpression or silencing of miR-34a inversely modulates expression of synaptic targets, including synaptotagmin-1 and syntaxin-1A. Notably, the axis TAp73/miR-34a/synaptotagmin-1 is conserved in brains from Alzheimer's patients. These data reinforce a role for TAp73 in neuronal development.
    Proceedings of the National Academy of Sciences 12/2011; 108(52):21093-8. · 9.81 Impact Factor
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    ABSTRACT: Ovarian serous borderline tumors (SBTs) are presumed to originate in the ovarian cortex or peritoneal surface. The pathogenetic role of the fallopian tube (FT) is unclear; however, recently, secretory cell outgrowths (SCOUTs) lacking PAX2 expression were described in benign FTs. This study addressed (1) the differentiation characteristics of SBTs and (2) the frequency of SCOUTs lacking PAX2 expression in the FTs of patients with SBTs and compared (3) SCOUT morphology and (4) PAX2 expression with SBTs. SBTs and FT epithelium shared both ciliated (p73) and secretory (HMFG2) differentiation. PAX2-null SCOUT frequency in FT cross-sections from patients with SBTs was 0.28 (110 of 398) versus 0.112 in benign hysterectomies and nearly 0 in pediatric and postpartum sterilization specimens (P = < 0.001). When adjusted for age, the differences narrowed but remained significant (P = 0.010). SCOUTs were heterogeneous, some displaying ciliated differentiation and papillary architecture. Two cases of discrete multifocal papillary SCOUTs in the FTs were associated with SBTs. All SBTs had heterogeneous PAX2 staining with areas of PAX2 loss. This study shows for the first time that PAX2-null SCOUTs are more common in the oviducts of women with SBTs and that loss of PAX2 expression occurs in most SBTs. These discoveries link both morphologic and functional gene (PAX2) alterations in the oviduct to SBTs, similar to that reported in high-grade serous carcinoma. Further study is warranted to clarify the relationship of the oviduct to serous neoplasia.
    The American journal of surgical pathology 12/2011; 35(12):1759-65. · 4.06 Impact Factor
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    ABSTRACT: With the exception of germ-line mutations in ovarian cancer susceptibility genes, genetic predictors for women destined for ovarian serous cancer cannot be identified in advance of malignancy. We recently showed that benign secretory cell outgrowths (SCOUTs) in the oviduct are increased in frequency with concurrent serous cancer and typically lack PAX2 expression (PAX2-null). The present study examined the relationship of PAX2-null SCOUTs to high-grade serous cancers by comparing oviducts from women with benign gynecologic conditions and high-grade serous cancers. PAX2-null SCOUTs were identified by immunostaining and computed as a function of location, frequency (F) per number of cross-sections examined, and age. Six hundred thirty-nine cross-sections from 35 serous cancers (364) and 35 controls (275) were examined. PAX2-null SCOUTs consisted of discrete linear stretches of altered epithelium ranging from cuboidal/columnar, to pseudostratified, the latter including ciliated differentiation. They were evenly distributed among proximal and fimbrial tubal sections. One hundred fourteen (F=0.31) and 45 (F=0.16) PAX2-null SCOUTs were identified in cases and controls, respectively. Mean individual case-specific frequencies for cases and controls were 0.39 and 0.14, respectively. SCOUT frequency increased significantly with age in both groups (P=0.01). However, when adjusted for age and the number of sections examined, the differences in frequency between cases and controls remained significant at P=0.006. This study supports a relationship between discrete PAX2 gene dysregulation in the oviduct and both increasing age and, more significantly, the presence of co-existing serous cancer. We propose a unique co-variable in benign oviductal epithelium-the PAX2-null SCOUT-that reflects underlying dysregulation in genes linked to serous neoplasia.
    Modern Pathology 11/2011; 25(3):449-55. · 5.25 Impact Factor

Publication Stats

14k Citations
1,539.37 Total Impact Points

Institutions

  • 2013
    • National University Health System
      Singapore
  • 2000–2013
    • Brigham and Women's Hospital
      • • Division of Women's and Perinatal Pathology
      • • Department of Pathology
      • • Department of Medicine
      Boston, MA, United States
  • 1970–2013
    • Harvard Medical School
      • Department of Cell Biology
      Boston, Massachusetts, United States
  • 2012
    • University of Liège
      Luik, Walloon Region, Belgium
  • 2011–2012
    • Genome Institute of Singapore
      Tumasik, Singapore
    • Institute of Medical Biology
      Tumasik, Singapore
  • 2010–2011
    • University of Leicester
      • Medical Research Council Toxicology Unit
      Leicester, ENG, United Kingdom
    • Partners HealthCare
      Boston, Massachusetts, United States
    • University of Michigan
      • Department of Pathology
      Ann Arbor, MI, United States
    • Dana-Farber Cancer Institute
      • Department of Cancer Biology
      Boston, MA, United States
  • 2008
    • Boston Children's Hospital
      Boston, Massachusetts, United States
  • 2007
    • Sungkyunkwan University
      • Department of Molecular and Cell Biology
      Seoul, Seoul, South Korea
  • 2004
    • National Cancer Center Korea
      Kōyō, Gyeonggi Province, South Korea
  • 2003
    • Pohang University of Science and Technology
      • Division of Molecular and Life Sciences
      Andong, North Gyeongsang, South Korea
    • University of Oregon
      Eugene, Oregon, United States
  • 2002
    • Radboud University Medical Centre (Radboudumc)
      • Department of Human Genetics
      Nymegen, Gelderland, Netherlands
  • 2001
    • Mackay Memorial Hospital
      T’ai-pei, Taipei, Taiwan
  • 1988–1993
    • Harvard University
      • Department of Molecular and Cell Biology
      Boston, MA, United States