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1.  VH1-44 gene usage defines a subset of canine B-cell lymphomas associated with better patient survival 
The use of specific immunoglobulin heavy chain variable region (VH) genes has been associated with increased patient survival in human B-cell lymphomas (hBCL). Given the similarity of human and canine BCL (cBCL) in morphology and clinical treatment, we examined the choice of VH in cBCL and determined whether VH gene selection was a distinct feature associated with survival time in dogs. VH gene selection and mutational status in 52 cBCL, including 29 diffuse large B-cell lymphomas (cDLBCL, the most common subtype of cBCL), were analyzed by comparison with the 80 published canine germline VH gene sequences. We further examined the prognostic impact of the subgroups defined by these features on canine survival. We found that VH1-44 was preferentially expressed in the majority of the 52 cBCLs (60%) as well as in the majority of the cDLBCL subset (59%). VH1-44 gene expression was associated with a statistically better overall survival (p=0.039) in cBCL patients, as well as in the cDLBCL subset of patients (p=0.038). These findings suggest that VH gene selection in cBCL is not random and may therefore have functional implications for cBCL lymphomagenesis, in addition to being a useful prognostic biomarker.
doi:10.1016/j.vetimm.2013.10.020
PMCID: PMC3923267  PMID: 24332568
immunoglobulin heavy chain variable region (VH); B-cell lymphoma; diffuse large B-cell lymphoma; survival; VH1-44
2.  Gene profiling of canine B-cell lymphoma reveals germinal center and post-germinal center subtypes with different survival times, modeling human DLBCL 
Cancer research  2013;73(16):5029-5039.
Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma subtype, and fewer than half of patients are cured with standard front-line therapy. To improve therapeutic options, better animal models that accurately mimic human DLBCL (hDLBCL) are needed. Canine DLBCL (cDLBCL), one of the most common cancers in veterinary oncology, is morphologically similar to hDLBCL and is treated using similar chemotherapeutic protocols. With genomic technologies, it is now possible to molecularly evaluate dogs as a potential large-animal model for hDLBCL. We evaluated canine B-cell lymphomas (cBCLs) using immunohistochemistry and gene expression profiling. Canine B-cell lymphoma expression profiles were similar in many ways to hDLBCLs. For instance, a subset had increased expression of NF-κB pathway genes, mirroring human activated B-cell (ABC)-type DLBCL. Furthermore, immunoglobulin heavy chain (IGH) ongoing mutation status, which is correlated with ABC/germinal center B-cell (GCB) cell of origin in hDLBCL, separated cBCL into two groups with statistically different progression-free and overall survival times. In contrast with hDLBCL, cBCL rarely expressed BCL6 and MUM1/IRF4 by immunohistochemistry. Collectively, these studies identify molecular similarities to hDLBCL that introduce pet dogs as a representative model of hDLBCL for future studies, including therapeutic clinical trials.
doi:10.1158/0008-5472.CAN-12-3546
PMCID: PMC3755352  PMID: 23783577
3.  Application of Multiplexed Kinase Inhibitor Beads to Study Kinome Adaptations in Drug-Resistant Leukemia 
PLoS ONE  2013;8(6):e66755.
Protein kinases play key roles in oncogenic signaling and are a major focus in the development of targeted cancer therapies. Imatinib, a BCR-Abl tyrosine kinase inhibitor, is a successful front-line treatment for chronic myelogenous leukemia (CML). However, resistance to imatinib may be acquired by BCR-Abl mutations or hyperactivation of Src family kinases such as Lyn. We have used multiplexed kinase inhibitor beads (MIBs) and quantitative mass spectrometry (MS) to compare kinase expression and activity in an imatinib-resistant (MYL-R) and -sensitive (MYL) cell model of CML. Using MIB/MS, expression and activity changes of over 150 kinases were quantitatively measured from various protein kinase families. Statistical analysis of experimental replicates assigned significance to 35 of these kinases, referred to as the MYL-R kinome profile. MIB/MS and immunoblotting confirmed the over-expression and activation of Lyn in MYL-R cells and identified additional kinases with increased (MEK, ERK, IKKα, PKCβ, NEK9) or decreased (Abl, Kit, JNK, ATM, Yes) abundance or activity. Inhibiting Lyn with dasatinib or by shRNA-mediated knockdown reduced the phosphorylation of MEK and IKKα. Because MYL-R cells showed elevated NF-κB signaling relative to MYL cells, as demonstrated by increased IκBα and IL-6 mRNA expression, we tested the effects of an IKK inhibitor (BAY 65-1942). MIB/MS and immunoblotting revealed that BAY 65-1942 increased MEK/ERK signaling and that this increase was prevented by co-treatment with a MEK inhibitor (AZD6244). Furthermore, the combined inhibition of MEK and IKKα resulted in reduced IL-6 mRNA expression, synergistic loss of cell viability and increased apoptosis. Thus, MIB/MS analysis identified MEK and IKKα as important downstream targets of Lyn, suggesting that co-targeting these kinases may provide a unique strategy to inhibit Lyn-dependent imatinib-resistant CML. These results demonstrate the utility of MIB/MS as a tool to identify dysregulated kinases and to interrogate kinome dynamics as cells respond to targeted kinase inhibition.
doi:10.1371/journal.pone.0066755
PMCID: PMC3691232  PMID: 23826126
4.  Temporal Trends in Presentation and Survival for HIV-Associated Lymphoma in the Antiretroviral Therapy Era 
Background
Lymphoma is the leading cause of cancer-related death among HIV-infected patients in the antiretroviral therapy (ART) era.
Methods
We studied lymphoma patients in the Centers for AIDS Research Network of Integrated Clinical Systems from 1996 until 2010. We examined differences stratified by histology and diagnosis year. Mortality and predictors of death were analyzed using Kaplan–Meier curves and Cox proportional hazards.
Results
Of 23 050 HIV-infected individuals, 476 (2.1%) developed lymphoma (79 [16.6%] Hodgkin lymphoma [HL]; 201 [42.2%] diffuse large B-cell lymphoma [DLBCL]; 56 [11.8%] Burkitt lymphoma [BL]; 54 [11.3%] primary central nervous system lymphoma [PCNSL]; and 86 [18.1%] other non-Hodgkin lymphoma [NHL]). At diagnosis, HL patients had higher CD4 counts and lower HIV RNA than NHL patients. PCNSL patients had the lowest and BL patients had the highest CD4 counts among NHL categories. During the study period, CD4 count at lymphoma diagnosis progressively increased and HIV RNA decreased. Five-year survival was 61.6% for HL, 50.0% for BL, 44.1% for DLBCL, 43.3% for other NHL, and 22.8% for PCNSL. Mortality was associated with age (adjusted hazard ratio [AHR] = 1.28 per decade increase, 95% confidence interval [CI] = 1.06 to 1.54), lymphoma occurrence on ART (AHR = 2.21, 95% CI = 1.53 to 3.20), CD4 count (AHR = 0.81 per 100 cell/µL increase, 95% CI = 0.72 to 0.90), HIV RNA (AHR = 1.13 per log10copies/mL, 95% CI = 1.00 to 1.27), and histology but not earlier diagnosis year.
Conclusions
HIV-associated lymphoma is heterogeneous and changing, with less immunosuppression and greater HIV control at diagnosis. Stable survival and increased mortality for lymphoma occurring on ART call for greater biologic insights to improve outcomes.
doi:10.1093/jnci/djt158
PMCID: PMC3748003  PMID: 23892362
5.  MOLECULAR SIGNATURES OF METASTASIS IN HEAD AND NECK CANCER 
Head & neck  2008;30(10):1273-1283.
Background
Metastases are the primary cause of cancer treatment failure and death, yet metastatic mechanisms remain incompletely understood.
Methods
We studied the molecular basis of head and neck cancer metastasis by transcriptionally profiling 70 samples from 27 patients—matching normal adjacent tissue, primary tumor, and cervical lymph node metastases.
Results
We identified tumor-associated expression signatures common to both primary tumors and metastases. Use of matching metastases revealed an additional 46 dysregulated genes associated solely with head and neck cancer metastasis. However, despite being metastasis-specific in our sample set, these 46 genes are concordant with genes previously discovered in primary tumors that metastasized.
Conclusions
Although our data and related studies show that most of the metastatic potential appears to be inherent to the primary tumor, they are also consistent with the notion that a limited number of additional clonal changes are necessary to yield the final metastatic cell(s), albeit in a variable temporal order.
doi:10.1002/hed.20871
PMCID: PMC4136479  PMID: 18642293
head and neck cancer; expression profiling; metastasis; gene signatures; oncogenomics
6.  G protein signaling modulator-3: a leukocyte regulator of inflammation in health and disease 
G protein signaling modulator-3 (GPSM3), also known as G18 or AGS4, is a member of a family of proteins containing one or more copies of a small regulatory motif known as the GoLoco (or GPR) motif. GPSM3 interacts directly with Gα and Gβ subunits of heterotrimeric G proteins to regulate downstream intracellular signals initiated by G protein coupled receptors (GPCRs) that are activated via binding to their cognate ligands. GPSM3 has a selective tissue distribution and is highly expressed in immune system cells; genome-wide association studies (GWAS) have recently revealed that single nucleotide polymorphisms (SNPs) in GPSM3 are associated with chronic inflammatory diseases. This review highlights the current knowledge of GPSM3 function in normal and pathologic immune-mediated conditions.
PMCID: PMC4138133  PMID: 25143870
GoLoco; G protein coupled receptor; GPSM3; chemokine; migration; rheumatoid arthritis
7.  Association of early HIV viremia with mortality after HIV-associated lymphoma 
AIDS (London, England)  2013;27(15):2365-2373.
Objective
To examine the association between early HIV viremia and mortality after HIV-associated lymphoma.
Design
Multicenter observational cohort study.
Setting
Center for AIDS Research Network of Integrated Clinical Systems cohort.
Subjects
HIV-infected patients with lymphoma diagnosed between 1996 and 2011, who were alive 6 months after lymphoma diagnosis and with ≥2 HIV RNA values during the 6 months after lymphoma diagnosis.
Exposure
Cumulative HIV viremia during the 6 months after lymphoma diagnosis, expressed as viremia copy-6-months.
Main outcome measure
All-cause mortality between 6 months and 5 years after lymphoma diagnosis.
Results
Of 224 included patients, 183 (82%) had non-Hodgkin lymphoma (NHL) and 41 (18%) had Hodgkin lymphoma (HL). At lymphoma diagnosis, 105 (47%) patients were on antiretroviral therapy (ART), median CD4 count was 148 cells/µlL (IQR 54– 322), and 33% had suppressed HIV RNA (<400 copies/mL). In adjusted analyses, mortality was associated with older age [adjusted hazard ratio (AHR) 1.37 per decade increase, 95% CI 1.03–1.83], lymphoma occurrence on ART (AHR 1.63, 95% CI 1.02– 2.63), lower CD4 count (AHR 0.75 per 100 cell/µL increase, 95% CI 0.64–0.89), and higher early cumulative viremia (AHR 1.35 per log10copies × 6-months/mL, 95% CI 1.11–1.65). The detrimental effect of early cumulative viremia was consistent across patient groups defined by ART status, CD4 count, and histology.
Conclusions
Exposure to each additional 1-unit log10 in HIV RNA throughout the 6 months after lymphoma diagnosis, was associated with a 35% increase in subsequent mortality. These results suggest that early and effective ART during chemotherapy may improve survival.
doi:10.1097/QAD.0b013e3283635232
PMCID: PMC3773290  PMID: 23736149
AIDS; Burkitt lymphoma; diffuse large B-cell lymphoma; HIV; Hodgkin lymphoma; lymphoma; non-Hodgkin lymphoma
8.  Clinical Presentation, Treatment, and Outcomes Among 65 Patients with HIV-Associated Lymphoma Treated at the University of North Carolina, 2000–2010 
Abstract
HIV increases risk of non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). The effect of HIV on presentation, treatment, and outcomes of NHL and HL in routine care in the combination antiretroviral therapy (cART) merits further characterization. We performed a retrospective analysis of HIV-infected patients with NHL and HL receiving care at the University of North Carolina at Chapel Hill from January 1, 2000 until December 31, 2010. Statistical analyses were conducted using SAS, version 9.2 (SAS Institute Inc). Sixty-five HIV-infected patients with NHL and HL were identified. Patients with non-CNS NHL and HL presented with advanced disease (85% stage III or IV) and adverse prognostic features. Patients completed 87% of planned chemotherapy cycles, and 68% of patients completed stage-appropriate therapy. Dose reduction, interruption, and/or delay occurred during more than 25% of administered cycles in 64% of patients. Infectious complications, febrile neutropenia, and myelosuppression accounted for 78% of deviations from planned cumulative dose and dose intensity. Primary CNS lymphoma (PCNSL) was associated with poor prognosis, but 2-year overall survival was 66% for all non-CNS lymphoma. Among patients surviving at least 2 years, 75% had CD4 count >200 cells/μl and 79% had HIV viral load <400 copies/ml at last follow-up. Despite advanced disease and difficulty tolerating chemotherapy with optimal cumulative dose and dose intensity, most patients with non-CNS HIV-associated lymphoma survived more than 2 years after diagnosis, the majority with suppressed HIV RNA.
doi:10.1089/aid.2011.0259
PMCID: PMC3399569  PMID: 22011066
9.  The genetic landscape of mutations in Burkitt lymphoma 
Nature genetics  2012;44(12):1321-1325.
Burkitt lymphoma is characterized by deregulation of MYC, but the contribution of other genetic mutations to the disease is largely unknown. Here, we describe the first completely sequenced genome from a Burkitt lymphoma tumor and germline DNA from the same affected individual. We further sequenced the exomes of 59 Burkitt lymphoma tumors and compared them to sequenced exomes from 94 diffuse large B-cell lymphoma (DLBCL) tumors. We identified 70 genes that were recurrently mutated in Burkitt lymphomas, including ID3, GNA13, RET, PIK3R1 and the SWI/SNF genes ARID1A and SMARCA4. Our data implicate a number of genes in cancer for the first time, including CCT6B, SALL3, FTCD and PC. ID3 mutations occurred in 34% of Burkitt lymphomas and not in DLBCLs. We show experimentally that ID3 mutations promote cell cycle progression and proliferation. Our work thus elucidates commonly occurring gene-coding mutations in Burkitt lymphoma and implicates ID3 as a new tumor suppressor gene.
doi:10.1038/ng.2468
PMCID: PMC3674561  PMID: 23143597
10.  Analysis of innate and acquired resistance to anti-CD20 antibodies in malignant and nonmalignant B cells 
PeerJ  2013;1:e31.
The anti-CD20 monoclonal antibody, rituximab, provides a significant therapeutic benefit for patients with B-cell disorders. However, response to therapy varies and relapses are common, so an understanding of both inherited and acquired rituximab resistance is needed. In order to identify mechanisms of inherited resistance, sensitive versus resistant individuals were selected from a survey of 92 immortalized lymphoblastoid B-cell lines from normal individuals. Levels of CD20 protein and surface expression were lower in the resistant group. In contrast, CD20 mRNA levels were not correlated with susceptibility, suggesting regulation at a post-transcriptional level. To examine acquired resistance, resistant sublines were selected from both lymphoblastoid as well as lymphoma cell lines. Confirming previous findings, there was significant down-regulation of CD20 protein expression in all the resistant sublines. CD20 mRNA splice variants are reported to be associated with development of resistance. Three splice variants were observed in our cell lines, each lacking the binding epitope for rituximab, but none were associated with rituximab resistance. The second generation anti-CD20 mAb, ofatumumab, was more active compared with rituximab in vitro in the survey of all B-cell lines, mirroring results that have been reported previously with malignant B-cells. These studies show that normal B-lymphoblastoid cell lines can be used to model both innate and acquired mechanisms of resistance. They validate the important role of CD20 expression and enable future genetic studies to identify additional mediators of anti-CD20 mAb resistance.
doi:10.7717/peerj.31
PMCID: PMC3628892  PMID: 23638367
Rituximab; Ofatumumab; CD20 expression; mRNA splice variants; Complement-dependent cytotoxicity; Drug resistance; Lymphoblastoid cell line
11.  Pharmacogenomic characterization of US FDA-approved cytotoxic drugs 
Pharmacogenomics  2011;12(10):1407-1415.
Aims
Individualization of cancer chemotherapy based on the patient’s genetic makeup holds promise for reducing side effects and improving efficacy. However, the relative contribution of genetics to drug response is unknown.
Materials & methods
In this study, we investigated the cytotoxic effect of 29 commonly prescribed chemotherapeutic agents from diverse drug classes on 125 lymphoblastoid cell lines derived from 14 extended families.
Results
The results of this systematic study highlight the variable role that genetics plays in response to cytotoxic drugs, ranging from a heritability of <0.15 for gemcitabine to >0.60 for epirubicin.
Conclusion
Putative quantitative trait loci for cytotoxic response were identified, as well as drug class-specific signatures, which could indicate possible shared genetic mechanisms. In addition to the identification of putative quantitative trait locis, the results of this study inform the prioritization of chemotherapeutic drugs with a sizable genetic response component for future investigation.
doi:10.2217/pgs.11.92
PMCID: PMC3399590  PMID: 22008047
cancer; cell line; chemotherapy; cytotoxicity; pharmacogenetics; pharmacogenomic; QTL
13.  Treatment of Kaposi Sarcoma-Associated Herpesvirus-Associated Cancers 
Kaposi sarcoma (KS) is the most frequent AIDS-defining cancer worldwide. KS-associated herpesvirus (KSHV) is the etiological agent of KS, and the virus is also associated with two lymphoproliferative diseases. Both KS and KSHV-associated lymphomas, are cancers of unique molecular composition. They represent a challenge for cancer treatment and an opportunity to identify new mechanisms of transformation. Here, we review the current clinical insights into KSHV-associated cancers and discuss scientific insights into the pathobiology of KS, primary effusion lymphoma, and multicentric Castleman’s disease.
doi:10.3389/fmicb.2012.00141
PMCID: PMC3328849  PMID: 22529843
KSHV; lymphoma; sarcoma; viral cancer; therapy
14.  Methylation of the Candidate Biomarker TCF21 Is Very Frequent Across A Spectrum of Early Stage Non-Small Cell Lung Cancers 
Cancer  2010;117(3):606-617.
Background
The transcription factor TCF21 is involved in mesenchymal-to-epithelial differentiation and was shown to be aberrantly hypermethylated in lung and head and neck cancers. Because of its reported high frequency of hypermethylation in lung cancer, we sought to characterize the stages and types of non-small cell lung cancer (NSCLC) that are hypermethylated and to define the frequency of hypermethylation and associated “second hits”.
Methods
We determined TCF21 promoter hypermethylation in 105 NSCLC including various stages and histologies in smokers and nonsmokers. Additionally, we examined TCF21 loss-of-heterozygosity and mutational status. We also assayed 22 cancer cell lines from varied tissue origins. We validated and expanded our NSCLC results by examining TCF21 immunohistochemical expression on a tissue microarray containing 300 NSCLC cases.
Results
Overall, 81% of NSCLC samples showed TCF21 promoter hypermethylation and 84% showed decreased TCF21 protein expression. Multivariate analysis showed that TCF21 expression, although below normal in both histologies, was lower in adenocarcinoma than squamous cell carcinoma, and was not independently correlated with gender, smoking and EGFR mutation status, or clinical outcome. Cell lines from other cancer types also showed frequent TCF21 promoter hypermethylation.
Conclusions
Hypermethylation and decreased expression of TCF21 were tumor-specific and very frequent in all NSCLC, even early-stage disease, thus making TCF21 a potential candidate methylation biomarker for early-stage NSCLC screening. TCF21 hypermethylation in a variety of tumor cell lines suggests it may also be a valuable methylation biomarker in other tumor types.
doi:10.1002/cncr.25472
PMCID: PMC3023841  PMID: 20945327
TCF21; methylation; biomarker; lung cancer; screening
16.  FLT3 mutations in canine acute lymphocytic leukemia 
BMC Cancer  2011;11:38.
Background
FMS-like tyrosine kinase 3 (FLT3) is a commonly mutated protein in a variety of human acute leukemias. Mutations leading to constitutively active FLT3, including internal tandem duplications of the juxtamembrane domain (ITD), result in continuous cellular proliferation, resistance to apoptotic cell death, and a poorer prognosis. A better understanding of the molecular consequences of FLT3 activation would allow improved therapeutic strategies in these patients. Canine lymphoproliferative diseases, including lymphoma and acute leukemias, share evolutionarily conserved chromosomal aberrations and exhibit conserved mutations within key oncogenes when compared to their human counterparts. A small percentage of canine acute lymphocytic leukemias (ALL) also exhibit FLT3 ITD mutations.
Methods
We molecularly characterized FLT3 mutations in two dogs and one cell line, by DNA sequencing, gene expression analysis via quantitative real-time PCR, and sensitivity to the FLT3 inhibitor lestaurtinib via in vitro proliferation assays. FLT 3 and downstream mediators of FLT3 activation were assessed by Western blotting.
Results
The canine B-cell leukemia cell line, GL-1, and neoplastic cells from 2/7 dogs diagnosed cytologically with ALL were found to have FLT3 ITD mutations and FLT3 mRNA up-regulation. Lestaurtinib, a small molecule FLT3 inhibitor, significantly inhibited the growth of GL-1 cells, while not affecting the growth of two other canine lymphoid cell lines without the FLT3 mutation. Finally, western blots were used to confirm the conserved downstream mediators of FLT3 activating mutations.
Conclusions
These results show that ALL and FLT3 biology is conserved between canine and human patients, supporting the notion that canine ALL, in conjunction with the GL-1 cell line, will be useful in the development of a relevant large animal model to aid in the study of human FLT3 mutant leukemias.
doi:10.1186/1471-2407-11-38
PMCID: PMC3040160  PMID: 21272320
17.  Genome-Wide Hypomethylation in Head and Neck Cancer Is More Pronounced in HPV-Negative Tumors and Is Associated with Genomic Instability 
PLoS ONE  2009;4(3):e4941.
Loss of genome-wide methylation is a common feature of cancer, and the degree of hypomethylation has been correlated with genomic instability. Global methylation of repetitive elements possibly arose as a defense mechanism against parasitic DNA elements, including retrotransposons and viral pathogens. Given the alterations of global methylation in both viral infection and cancer, we examined genome-wide methylation levels in head and neck squamous cell carcinoma (HNSCC), a cancer causally associated with human papilloma virus (HPV). We assayed global hypomethylation levels in 26 HNSCC samples, compared with their matched normal adjacent tissue, using Pyrosequencing-based methylation assays for LINE repeats. In addition, we examined cell lines derived from a variety of solid tumors for LINE and SINE (Alu) repeats. The degree of LINE and Alu hypomethylation varied among different cancer cell lines. There was only moderate correlation between LINE and Alu methylation levels, with the range of variation in methylation levels being greater for the LINE elements. LINE hypomethylation was more pronounced in HPV-negative than in HPV-positive tumors. Moreover, genomic instability, as measured by genome-wide loss-of-heterozygosity (LOH) single nucleotide polymorphism (SNP) analysis, was greater in HNSCC samples with more pronounced LINE hypomethylation. Global hypomethylation was variable in HNSCC. Its correlation with both HPV status and degree of LOH as a surrogate for genomic instability may reflect alternative oncogenic pathways in HPV-positive versus HPV-negative tumors.
doi:10.1371/journal.pone.0004941
PMCID: PMC2654169  PMID: 19293934
18.  Structure–Function Relationships in Yeast TubulinsD⃞ 
Molecular Biology of the Cell  2000;11(5):1887-1903.
A comprehensive set of clustered charged-to-alanine mutations was generated that systematically alter TUB1, the major α-tubulin gene of Saccharomyces cerevisiae. A variety of phenotypes were observed, including supersensitivity and resistance to the microtubule-destabilizing drug benomyl, lethality, and cold- and temperature-sensitive lethality. Many of the most benomyl-sensitive tub1 alleles were synthetically lethal in combination with tub3Δ, supporting the idea that benomyl supersensitivity is a rough measure of microtubule instability and/or insufficiency in the amount of α-tubulin. The systematic tub1 mutations were placed, along with the comparable set of tub2 mutations previously described, onto a model of the yeast α–β-tubulin dimer based on the three-dimensional structure of bovine tubulin. The modeling revealed a potential site for binding of benomyl in the core of β-tubulin. Residues whose mutation causes cold sensitivity were concentrated at the lateral and longitudinal interfaces between adjacent subunits. Residues that affect binding of the microtubule-binding protein Bim1p form a large patch across the exterior-facing surface of α-tubulin in the model. Finally, the positions of the mutations suggest that proximity to the α–β interface may account for the finding of synthetic lethality of five viable tub1 alleles with the benomyl-resistant but otherwise entirely viable tub2-201 allele.
PMCID: PMC14891  PMID: 10793159

Results 1-18 (18)