Biomedical subjects

Wendy Liu

Publications and source records attributed to Wendy Liu.

15 recordsLinked to original sources

PubMed2006

Distinct clinical and pathological features are associated with the BRAF(T1799A(V600E)) mutation in primary melanoma.

The BRAF(T1799A) mutation encodes BRAF(V600E) that leads to activation of the mitogen-activated protein kinase pathway. This study aimed to assess the clinico-pathological features of primary invasive melanomas containing the BRAF(T1799A) mutation. Patients (n=251) with invasive primary melanomas from Australia were interviewed and examined with respect to their melanoma characteristics and risk factors. Independent review of pathology, allele-specific PCR for the BRAF(T1799A) mutation, immunohistochemical staining with Ki67, and phospho-histone-H3 (PH3) were performed. The BRAF(T1799A) mutation was found in 112 (45%) of the primary melanomas. Associations with the BRAF(T1799A) mutation (P<0.05) were as follows: low tumor thickness (odds ratio (OR)=3.3); low mitotic rate (OR=2.0); low Ki67 score (OR=5.0); low PH3 score (OR=3.3); superficial spreading melanoma (OR=10.0); pigmented melanoma (OR=3.7); a lack of history of solar keratoses (OR=2.7); a location on the trunk (OR=3.4) or extremity (OR=2.0); a high level of self-reported childhood sun exposure (OR=2.0); < or =50 years of age (OR=2.5); and fewer freckles (OR=2.5). We conclude that the BRAF(T1799A) mutation has associations with host phenotype, tumor location, and pigmentation. Although implicated in the control of the cell cycle, the BRAF(T1799A) mutation is associated with a lower rate of tumor proliferation.

Adolescent↗

PubMed2006

Tumour suppressor function of RNase L in a mouse model.

RNase L is one of the key enzymes involved in the molecular mechanisms of interferon (IFN) actions. Upon binding with its activator, 5'-phosphorylated, 2'-5' oligoadenylates (2-5A), RNase L plays an important role in the antiviral and anti-proliferative functions of IFN, and exerts proapoptotic activity independent of IFN. In this study, we have found that RNase L retards proliferation in an IFN-dependent and independent fashion. To directly measure the effect of RNase L on tumour growth in the absence of other IFN-induced proteins, human RNase L cDNA was stably expressed in P-57 cells, an aggressive mouse fibrosarcoma cell line. Three clonal cell lines were isolated in which the overexpression of RNase L was 15-20-fold of the endogenous level. Groups of five nude mice were injected subcutaneously with either the human RNase L overexpressing clones (P-RL) or control cells transfected with an empty vector (P-Vec). Tumour growth by the two cell lines was monitored by measuring tumour volumes. In the P-RL group, tumour formation was significantly delayed and the tumours grew much slower compared to the control group. Morphologically, the P-RL tumour appeared to have more polygonal cells and increased single cell tumour necrosis. Interestingly, P-RL tumours eventually started to grow. Further analysis revealed, however, that these tumours no longer expressed ectopic RNase L. Our findings suggest that RNase L plays a critical role in the inhibition of fibrosarcoma growth in nude mice.

Animals↗

PubMed2006

Rate of growth in melanomas: characteristics and associations of rapidly growing melanomas.

OBJECTIVES: To investigate the spectrum of growth rates in melanomas and to identify clinical associations of rapidly growing melanomas. DESIGN: Clinical interview, skin examination, and pathology review. SETTING: Three tertiary melanoma referral centers and 2 private dermatology practices. PATIENTS: A total of 404 consecutive patients with invasive primary cutaneous melanomas. MAIN OUTCOME MEASURE: A surrogate for rate of growth in primary invasive melanoma was calculated as the ratio of Breslow thickness to time to melanoma development based on a previously reported assessment tool. RESULTS: One third of the melanomas grew 0.5 mm per month or more. The median monthly growth rate was 0.12 mm for superficial spreading melanomas, 0.13 mm for lentigo maligna melanomas, and 0.49 mm for nodular melanomas. Rapid tumor growth was associated with tumor thickness ( 4 mm, GMR = 12.1) and mitotic rate (<1/mm(2), GMR = 1.0; 1-4/mm(2), GMR = 2.9; 5-10/mm(2), GMR = 6.1; and >10/mm(2), GMR = 9.7). Rapid tumor growth occurred more often in males (GMR = 1.7), elderly individuals (>or=70 years old, GMR = 2.8), and patients with fewer melanocytic nevi (n<50, GMR = 2.0) and fewer freckles (GMR = 2.5). Rapidly growing melanomas were more often symmetrical (GMR = 2.5), elevated (GMR = 1.4), amelanotic (GMR = 1.7), regular in border (GMR = 2.5), and symptomatic (GMR = 1.7). CONCLUSIONS: Rapid growth of primary cutaneous melanomas is associated with aggressive histologic features and atypical clinical features. It occurs more frequently in elderly men and individuals with fewer nevi and fewer freckles.

Adolescent↗

PubMed2006

Risk factors for diseases of ileal pouch-anal anastomosis after restorative proctocolectomy for ulcerative colitis.

BACKGROUND & AIMS: Although pouchitis is considered the most common adverse sequela of ileal pouch-anal anastomosis (IPAA), inflammatory and noninflammatory conditions other than pouchitis are increasingly being recognized. The risk factors for these non-pouchitis conditions, including Crohn's disease (CD) of the pouch, cuffitis, and irritable pouch syndrome (IPS), have not been studied. The aim of this study was to assess risk factors for inflammatory and noninflammatory diseases of IPAA in a tertiary care setting. METHODS: The study consisted of 240 consecutive patients who were classified as having healthy pouches (N = 49), pouchitis (N = 61), CD of the pouch (N = 39), cuffitis (N = 41), or IPS (N =50). Demographic and clinical features were assessed to determine risk factors for each of these conditions by using logistic regression analysis. RESULTS: Risk factors remaining in the final logistic regression models were for pouchitis: IPAA indication for dysplasia (odds ratio [OR], 3.89; 95% confidence interval [CI], 1.69-8.98), never having smoked (OR, 5.09; 95% CI, 1.01-25.69), no use of anti-anxiety agents (OR, 5.19; 95% CI, 1.45-18.59), or use of NSAIDs (OR, 3.24; 95% CI, 1.71-6.13); for CD of the pouch: a long duration of IPAA (OR, 1.20; 95% CI, 1.12-1.30) and current smoking (OR, 4.77; 95% CI, 1.39-16.25); for cuffitis: arthralgias (OR, 4.13; 95% CI, 1.91-8.94) and younger age (OR, 1.16; 95% CI, 1.01-1.33); and for IPS: use of antidepressants (OR, 4.17, 95% CI, 1.95-8.92) or anti-anxiety agents (OR, 3.21; 95% CI, 1.34-7.47). CONCLUSIONS: The majority of risk factors for the 4 inflammatory and noninflammatory conditions of IPAA are different, suggesting that each of these diseases has a different etiology and pathogenesis. The identification and modification of these risk factors might help patients and clinicians to make a preoperative decision for IPAA, reduce IPAA-related morbidity, and improve response to treatment.

Adult↗

PubMed2005

Discovery and evaluation of 2-anilino-5-aryloxazoles as a novel class of VEGFR2 kinase inhibitors.

A series of derivatives of 2-anilino-5-phenyloxazole (5) has been identified as inhibitors of VEGFR2 kinase. Herein we describe the structure-activity relationship (SAR) of this novel template. Optimization of both aryl rings led to very potent inhibitors at both the enzymatic and cellular levels. Oxazole 39 had excellent solubility and good oral PK when dosed as the bis-mesylate salt and demonstrated moderate in vivo efficacy against HT29 human colon tumor xenografts. X-ray crystallography confirmed the proposed binding mode, and comparison of oxazoles 39 and 46 revealed interesting differences in orientation of 2-pyridyl and 3-pyridyl rings, respectively, attached at the meta position of the 5-phenyl ring.

Adenosine Triphosphate↗

PubMed2005

Intercellular junctions in Ewing sarcoma/primitive neuroectodermal tumor: additional evidence of epithelial differentiation.

Ewing sarcoma/primitive neuroectodermal tumor (ES/PNET) has recently been shown to frequently express cytokeratins, suggesting partial epithelial differentiation. Older ultrastructural studies have documented primitive cell-cell junctions in ES/PNET, reportedly resembling poorly formed desmosomes. Recently, paraffin-reactive antibodies have become available to proteins found in a variety of intercellular junctions indicative of epithelial differentiation, including tight junctions, desmosomes and adherens junctions. We examined intercellular junction protein expression in a large number of genetically confirmed ES/PNET. Formalin-fixed, paraffin-embedded sections from 23 primary and seven recurrent or metastatic cases of genetically confirmed ES/PNET were immunostained for claudin-1 and occludin (tight junction structural proteins), zonula occludens-1 (ZO-1, tight junction linker protein), desmoglein 1/2 (desmosomal adherens protein), desmoplakin (desmosomal structural protein) and E-cadherin (epithelial adherens junction protein), using steam heat-induced epitope retrieval and the Dako Envision system. Cases with >5% positive cells were scored as 'positive'. Normal colonic epithelium and skin served as external positive controls. Claudin-1 was expressed by 19 of 30 specimens (63%), ZO-1 was expressed by 15 of 29 specimens (51%), and occludin was expressed by three of 28 specimens (11%). In 28 specimens all three tight junction markers were evaluable. In all, 15 samples (54%) expressed only one tight junction marker, and 10 samples (36%) expressed two tight junction markers. No case expressed all three tight junction markers. Desmoglein was expressed in one of 30 (3%) samples. Desmoplakin was expressed in two of 28 (7%) samples. E-cadherin was negative in all cases. Our data suggest that many of the previously described cell-cell junctions in ES/PNET are poorly formed tight junctions, given the high frequency of claudin-1 and ZO-1 expression. This may underestimate the true frequency of tight junction protein expression in ES/PNET, as there are at least 20 different claudins and other ZO proteins. These tight junctions are almost certainly abnormal, given the absence of occludin expression in most cases. Desmosomal and adherens junction protein expression was rare to absent. Our findings provide additional evidence that ES/PNET frequently show partial epithelial differentiation.

Bone Neoplasms↗

PubMed2005

What features do patients notice that help to distinguish between benign pigmented lesions and melanomas?: the ABCD(E) rule versus the seven-point checklist.

The ABCD(E) rule and the seven-point checklist are diagnostic aids that have proven to be useful in the hands of physicians; however, little is known of their value to patients with respect to aiding self-detection. The objective of this study was to investigate features that patients notice when identifying melanomas and to explore how well these features correspond to the ABCD(E) rule and the seven-point checklist. A retrospective, modified, case-control study involving patient interviews was performed. All interviews were conducted through the private consulting rooms of a Melbourne dermatologist (JWK) and a Newcastle plastic surgeon (CH) prior to the result of pathology being known to the patients and the interviewers. Sixty-seven patients with benign pigmented skin lesions and 46 patients with melanomas were included. Using a logistic regression model, the change in size/new lesion and change in colour (major criteria, seven-point checklist) were most useful in differentiating between melanomas and benign pigmented lesions in the hands of patients [odds ratio (OR), 4.74; 95% confidence interval (CI), 1.85-12.19; P=0.001; OR, 4.27; 95% CI, 1.62-11.26; P=0.003, respectively). The ABCD(E) rule failed to discriminate between melanoma and other benign pigmented skin lesions. It can be concluded that, of the patients' observations, changes in size or colour were most important in distinguishing between benign pigmented lesions and melanomas. Such features therefore deserve emphasis in public education campaigns. Medical professionals should also remember to seek a history of change in assessing pigmented skin lesions.

Case-Control Studies↗

PubMed2005

Comprehensive evaluation of inflammatory and noninflammatory sequelae of ileal pouch-anal anastomoses.

BACKGROUND AND AIMS: Ileal pouch-anal anastomosis (IPAA) improves quality of life (QOL) for ulcerative colitis patients who require surgery. Crohn's disease (CD) of the pouch, pouchitis, cuffitis, and irritable pouch syndrome (IPS) have an adverse impact on physical and psychological well-being, which can compromise the gain in QOL after the surgery. Their clinical, endoscopic, and histologic features have not been fully characterized. The aim of this study was to compare demographic, clinical, endoscopic, and histologic features between CD of the pouch, pouchitis, cuffitis, IPS, and normal pouches. METHODS We enrolled 124 patients: normal pouches (N = 26), CD of the pouch (N = 23), pouchitis (N = 22), cuffitis (N = 21), and IPS (N = 32). Symptomatology, endoscopy, histology, and the Cleveland Global QOL and the Irritable Bowel Syndrome-QOL scores were compared among the groups. RESULTS: Univariate analysis of demographic and clinical data showed a possible association between NSAID use and pouchitis, extraintestinal manifestation and cuffitis, and antidepressant use and IPS. There were no differences in the Pouchitis Disease Activity Index symptom scores between the disease groups, with an exception of bleeding, which occurred almost exclusively in cuffitis. Endoscopy was useful in discriminating between CD of the pouch, pouchitis, cuffitis, and normal pouches or IPS. Patients with diseased IPAA had worse QOL scores. CONCLUSIONS: Symptoms largely overlapped among the disease groups of IPAA. Endoscopy is valuable for diagnosis. Inflammatory or noninflammatory sequelae of IPAA adversely affected patients' QOL.

Adult↗

PubMed2005

Morphologic and immunophenotypic diversity in Ewing family tumors: a study of 66 genetically confirmed cases.

More than 85% of Ewing sarcoma/primitive neuroectodermal tumor (ES/PNET), or "Ewing family of tumors" (EFTs), have the translocation, t (11;22) (q24;q12), with others having variant translocations. Identification of these by cytogenetic and/or molecular genetic techniques is specific for EFT and is increasingly recognized as the "gold standard" for diagnosis. However, these techniques are not universally available. We therefore studied a large group of genetically confirmed EFTs to more completely understand the morphologic and immunophenotypic spectrum of this rare sarcoma. Sixty-six cytogenetically, FISH or RT-PCR proven-EFTs were retrieved. In 56 cases, immunohistochemistry (IHC) was performed for pan-cytokeratins (PanCK), high molecular weight cytokeratins (HMWCK), desmin (DES), CD99, CD117, and FLI1 protein using heat-induced epitope retrieval and the Dako Envision system. The cases arose chiefly in children and young adults (median 18 years; range, 3-65 years) of both sexes (male, 32; female, 31; unknown, 3) in a variety of bone (N = 39) and soft tissue (N = 27) sites. Histologically, 46 cases (73%) showed only typical features of ES, 9 cases (16%) showed features of PNET, 3 cases (5%) showed "adamantinoma-like" features, 3 cases (5%) corresponded to "atypical Ewing sarcoma," 3 cases (5%) showed principally intersecting fascicles of spindled cells, and 2 cases had abundant hyalinized matrix. IHC results were as follows: PanCK (18 of 56, 32%), HMWCK (3 of 55, 5%), DES (1 of 56, 2%), CD99 (52 of 52, 100%), CD117 (13 of 54, 24%), and FLI1 (44 of 47, 94%). HMWCK was expressed only in "adamantinoma-like" EFTs, none of which expressed DES. In conclusion, most, but not all, EFTs can be accurately diagnosed using time-honored morphologic criteria and ancillary immunohistochemistry. However, genetic confirmation remains essential for the diagnosis of unusual morphologic variants of EFT, including "adamantinoma-like," spindled, sclerosing, and clear cell/anaplastic variants. Therefore, to exclude or confirm the diagnosis of Ewing's sarcoma in round cell sarcomas having a variety of patterns but not specifically conforming to a tumor of known lineage (eg, rhabdomyosarcoma), cytogenetics, and/or molecular analysis is required.

12E7 Antigen↗

PubMed2004

Endoscopic balloon dilation of ileal pouch strictures.

BACKGROUND: Restorative proctocolectomy with ileal pouch-anal anastomosis is the surgical treatment of choice in patients with ulcerative colitis. Strictures can occur at the inlet and outlet of the pouch. Endoscopic balloon dilation has been successfully used in patients with Crohn's strictures at the small intestine and colon. There are no published trials on endoscopic balloon therapy of ileal pouch strictures. AIM: To evaluate outpatient endoscopic balloon dilation of strictures in ileal pouches. METHODS: Patients underwent nonfluoroscopy-guided, nonsedated, outpatient endoscopic dilations with an 8.6-mm upper endoscope and through-the-scope balloons (size: 11-18 mm). Pre- and posttreatment Pouchitis Disease Activity Index symptom scores (range: 0-6), endoscopic stricture scores based on resistance in passing the endoscope (range: 0-4), and Cleveland Global Quality of Life were compared. RESULTS: Nineteen patients with pouch strictures who had concurrent Crohn's disease of the pouch (n = 11), cuffitis (n = 5), and pouchitis (n = 3), including 14 inlet and 14 outlet strictures, were enrolled. The mean number of strictures for each patient was 1.61 +/- 0.78. All strictures were successfully dilated with the through-the-scope balloon, with a mean of 1.74 +/- 1.19 (range: 1-5) sessions for each patient. Nine patients had a second endoscopy at 8 wk and five patients had a third pouch endoscopy at 16 wk after the initial endoscopic dilation. Endoscopic stricture scores immediately (0.30 +/- 0.47), 8 wk (0.40 +/- 0.51), and 16 wk (0.44 +/- 0.76) after the dilation were significantly improved compared to the predilation stricture scores (2.67 +/- 0.78). The symptom scores and quality-of-life (QOL) scores improved at week 8 and 16 following dilation, with a mean follow-up of 6.10 +/- 5.83 months (2-25 months). No complications were experienced with the procedure. One patient with CD who failed endoscopic and medical therapy underwent pouch resection. CONCLUSION: In conjunction with medical therapy, outpatient endoscopic balloon dilation appears safe and effective in treating pouch inlet and outlet strictures, by relieving symptoms, restoring pouch patency, and improving QOL in the majority of patients.

Adult↗

PubMed2003

Point mutations in or near the antigen-binding groove of HLA-DR3 implicate class II-associated invariant chain peptide affinity as a constraint on MHC class II polymorphism.

During maturation of MHC II molecules, newly synthesized and assembled complexes of MHC II alphabeta dimers with invariant chain (Ii) are targeted to endosomes, where Ii is proteolyzed, leaving remnant class II-associated Ii peptides (CLIP) in the MHC II peptide binding groove. CLIP must be released, usually with assistance from the endosomal MHC II peptide exchange factor, HLA-DM, before MHC II molecules can bind endosomal peptides. Structural factors that control rates of CLIP release remain poorly understood, although peptide side chain-MHC II specificity pocket interactions and MHC II polymorphism are important. Here we report that mutations betaS11F, betaS13Y, betaQ70R, betaK71E, betaK71N, and betaR74Q, which map to the P4 and P6 pockets of the groove of HLA-DR3 molecules, as well as alphaG20E adjacent to the groove, are associated with elevated CLIP in cells. Most of these mutations increase the resistance of CLIP-DR3 complexes to dissociation by SDS. In vitro, the groove mutations increase the stability of CLIP-DR3 complexes to dissociation. Dissociation rates in the presence of DM, as well as coimmunoprecipitation of some mutant DR3 molecules with DM, are also diminished. The profound phenotypes associated with some of these point mutations suggest that the need to maintain efficient CLIP release represents a constraint on naturally occurring MHC II polymorphism.

Amino Acid Substitution↗

PubMed2003

Pasteurella multocida urinary tract infection with molecular evidence of zoonotic transmission.

We describe a patient with a urinary tract infection (UTI) caused by Pasteurella multocida. Pulsed-field gel electrophoresis revealed that the clinical isolate recovered from the patient was identical (100% band match) to P. multocida isolates recovered from the patient's cat, but the isolate differed from an isolate recovered from a visiting cat and from a laboratory control strain. The patient also had abnormal urologic anatomy secondary to surgery; this has also been associated with P. multocida UTI.

Animals↗

PubMed2003

Interobserver variability in determining MIB-1 labeling indices in oligodendrogliomas.

Several studies have shown that MIB-1 labeling indices correlate well with tumor grade and prognosis in a variety of tumor types. Several factors are responsible for some degree of variability in the determination of labeling indices. Interobserver variability is one of the factors often cited as responsible for this variability. A slide from each of 30 oligodendrogliomas, stained with MIB-1 antibody, was distributed to six pathologists. The same set of slides was reviewed by each individual. Each pathologist was instructed to determine a MIB-1 labeling index by evaluating 1,000 tumor cell nuclei from the area of the slide with the most staining. The labeling index record reflected a percentage of positive-staining tumor cells. Interobserver agreement was compared. MIB-1 labeling indices ranged from 0 to 45.7. Overall agreement was good (> or =0.75) with a concordance coefficient of 0.832 (confidence interval, 0.700 to 0.909). Variability was greater among tumors with higher labeling indices as compared with tumors with labeling indices closer to 0. The overall agreement of MIB-1 labeling indices, while not perfect, was good. The generally minor variability among observers may be related to differences in the area of the slide evaluated and in differing lower thresholds for interpreting positivity. Further improvement of concordance may theoretically be attainable by further training and discussion among observers.

Biomarkers, Tumor↗

PubMed2002

The pathogenesis of pseudoachalasia: a clinicopathologic study of 13 cases of a rare entity.

Pseudoachalasia is an esophageal motor disorder usually associated with malignancy that has clinical, radiographic, and manometric findings that are often indistinguishable from primary achalasia. There are few reports examining the histologic features of the associated neoplasms and their relationship with the esophageal myenteric plexus. We studied the clinical and pathologic features of 13 cases of pseudoachalasia seen at our institution between 1979 and 1999. Detailed clinical and radiographic data were obtained from medical records. In all cases available histologic material was reviewed to confirm the presence and type of associated neoplasm. When possible, the relationship of the neoplasm to the esophageal myenteric plexus was examined. In selected cases immunohistochemical stains were performed to further evaluate this relationship. All patients had clinical, radiographic, and manometric features similar to primary achalasia. The cohort included seven men and six women, age range 24-79 years (median 61 years). Associated neoplasms included esophageal adenocarcinoma arising in Barrett's esophagus (n = 1), adenocarcinoma of the esophagogastric junction (n = 7), metastatic renal cell carcinoma to the esophagogastric junction (n = 1), breast adenocarcinoma (n = 1), pulmonary small cell carcinoma (n = 1), pleural malignant mesothelioma (n = 1), and mediastinal fibrosis (n = 1). The mechanism of pseudoachalasia was consistent with neoplastic infiltration of the esophageal myenteric plexus in 11 cases. Neoplastic cells surrounded myenteric ganglion cells, which appeared normal in number and morphology. In the patient with pulmonary small cell carcinoma, there was no evidence of neoplastic infiltration of the esophagogastric junction, and anti-ANNA-1 antibody was detected, suggesting a paraneoplastic syndrome. Tissue obtained at the time of esophagomyotomy revealed lymphocytic myenteric inflammation and marked depletion of ganglion cells identical to that seen in primary achalasia. The mechanism pseudoachalasia in the patient with breast adenocarcinoma is uncertain, as there was no evidence of direct involvement of the esophagogastric junction. In summary, we describe 13 cases of pseudoachalasia resulting in a clinical syndrome indistinguishable from primary achalasia. The most common mechanism is direct involvement of the esophageal myenteric plexus by neoplastic cells. Rarely, a distant neoplasm may cause this syndrome as a paraneoplastic process.

Adenocarcinoma↗

PubMedDate not supplied

Simple approach to micropattern cells on common culture substrates by tuning substrate wettability.

The ability to spatially control cell adhesion and multicellular organization is critical to many biomedical and tissue-engineering applications. This work describes a straightforward method to micropattern cells onto glass, silicone rubber, and polystyrene using commercially available reagents. An elastomeric polydimethylsiloxane stamp is used to contact-transfer extracellular matrix protein onto a surface followed by blocking cell adhesion in the surrounding regions by the physisorption of Pluronic surfactants. Using self-assembled monolayers of alkanethiols on gold as model surfaces to control surface wettability, we found that protein printing was most effective at intermediate to highly wetting surfaces whereas Pluronic adsorption occurred at intermediate to low wetting surfaces. Within a regimen of intermediate wettability both techniques were applied in conjunction to restrict cell adhesion to specified patterns. Adjusting the wettability of common tissue culture substrates to the same intermediate range again allowed the micropatterning of cells, suggesting that this approach is likely to be generally applicable to many types of materials. This technique therefore may allow for wider adoption of cell patterning.

Adsorption↗