{'fraction_non_alphanumeric': 0.03669054231837451, 'fraction_numerical': 0.02284022803683672, 'mean_word_length': 5.272060508824204, 'pattern_counts': {'":': 0, '<': 5, '<?xml version=': 0, '>': 3, 'https://': 1, 'lorem ipsum': 0, 'www.': 2, 'xml': 0}, 'pii_count': 1, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Targeting Thyrointegrin αvβ3 Using Fluorobenzyl Polyethylene Glycol Conjugated Tetraiodothyroacetic Acid (NP751) in Acute Myeloid Leukemia

Background Acute myeloid leukemia (AML) is associated with poor long-term survival, even with newer therapeutic agents. Here, we show the results of our preclinical study, in which we evaluated the efficacy of a new thyrointegrin αvβ3 antagonist, named fluorobenzyl polyethylene glycol conjugated tetraiodothyroacetic acid (fb-PMT). Methods and Results fb-PMT (NP751) is a potent αvβ3 antagonist of molecular weight of 2,478.9 Da. it represents a conjugate of tetraiodothyroacetic acid (tetrac) and monodisperse polyethylene glycol (PEG36), with a 4-fluorobenzyl group capping the other end of the PEG. fb-PMT effectively suppresses the malignant growth of human acute myeloid leukemia (AML) after successful engraftment in transgenic NSG-S xenograft mouse models of either established human AML cell line or primary AML cells. Daily treatment with fb-PMT (1–10 mg/kg body weight) subcutaneously (s.c.) for 3–4 weeks was associated with marked regression of leukemogenesis and extended survival in both models. The efficiency of the fb-PMT therapy was verified using in vivo imaging system (IVIS) imaging, flow cytometry, and histopathological examination to monitor the engraftment of leukemic cells in the bone marrow and other organs. fb-PMT therapy for 3–4 weeks at 3 and 10 mg/kg daily doses exhibited significant reduction (p < 0.0001) of leukemic cell burden of 74% and >95%, respectively. All fb-PMT-treated mice in the 10 mg/kg treatment arm successfully maintained remission after discontinuing the daily treatment. Comprehensive fb-PMT safety assessments demonstrated excellent safety and tolerability at multiple folds above the anticipated human therapeutic doses. Lastly, our genome-wide microarray screens demonstrated that fb-PMT works through the molecular interference mechanism with multiple signaling pathways contributing to growth and survival of leukemic cells. Conclusion Our preclinical findings of the potent anticancer activities of fb-PMT and its favorable safety profiles warrant its clinical investigation for the effective and safe management of AML.


INTRODUCTION
Acute myeloid leukemia (AML) is one of the most aggressive malignant hematological disorders. More than 20,000 new cases were estimated to occur in the United States in 2021 (33.0% of all kinds of new leukemia cases) (1). In 2021, the estimated number of deaths from AML is 11,400, which represents 56.32% of new cases (1.0% of all cancer deaths), with an overall 5-year survival rate of 27%. Average age of diagnosis with AML is about 68 years (1). Current treatment regimens for AML include traditional chemotherapy, allogeneic hematopoietic cell transplantation, and targeted therapies for specific mutations in limited numbers of AML patients [e.g., Midostaurin, a FLT3 inhibitor, first gene mutation-targeted therapeutic agent approved by Food and Drug Administration (FDA) 2017], all of whom still suffer from adverse effects and relapse (2,3). New broad spectrum effective and safe treatment options are urgently needed for the different types of AML.
According to the World Health Organization report in 2019, AML is now curable in up to 40% of patients under the age of 60 years and in up to 15% of patients over the age of 60. In elderly patients who are unable to tolerate the available chemotherapy, mean survival is 5-10 months (1, 4). Important advances in defining the "genomic landscape" of AML have enabled the prognostic classification of the disease and, to some extent, have facilitated the choice of chemotherapeutic agents. Among the mutations of particular interest and importance in AML are those of the FLT3, NPM, CEBPA, KIT, NRAS, IDH1/2, and TP53 genes (5). Targeted therapies for specific mutations in treating AML were recently approved by the FDA based on the genetic basis of the disease in different subsets of AML patients. However, those targeted therapies treat only a small percentage of the AML population, and patients suffer from relapse upon discontinuation of treatment (3).
On the other hand, crosstalk between leukemic cells and the bone marrow microenvironment is recognized as one of important factors that keeps leukemic cells in quiescent state and helps them to escape the different therapies. One of the functionally important entities in the bone marrow microenvironment is represented by the integrins. Integrins are a family of heterodimeric structural proteins of the plasma membrane that are important to cell-cell interactions and cell motility (6,7). They are critical to leukocytes' function and to the angiogenesis process, particularly local release of growth factors that are generously overexpressed and produced by cancer cells and by dividing endothelial cells of tumor-relevant blood vessels. There are different members of the integrin family including avb3, avb5, and a5b1 that are involved in angiogenesis and have high affinity to arginine-glycine-aspartate (RGD) extracellular matrix (ECM)-containing angiogenesis modulators such as fibronectin, fibrinogen, and ostepontin (8)(9)(10). avb3 (thyrointegrin) is generously expressed by cancer cells and by dividing endothelial cells. Mechanistically, thyrointegrin avb3 enhances b-catenin signaling and the tyrosine kinase activities in AML (11,12). Integrin avb3 was reported to be highly expressed in AML and associated with poor outcomes (13,14).
This study focused on comprehensive preclinical evaluations of anticancer activities of a novel thyrointegrin avb3 antagonist, fb-PMT in models of AML. Mechanistically, fb-PMT and similar molecules bind to a specific site on thyrointegrin avb3 receptors that can be blocked with high affinity by various triazole tetrac derivatives (15)(16)(17)(18). Our genome-wide microarray screens demonstrated that fb-PMT appears to exert its potent anticancer actions on human AML through a molecular interference mechanism with multiple signaling pathways supporting growth and survival of leukemic cells.

Tumor Cells and Test Compound
AML cell lines (K562-Luc; human erythroleukemia cells and KG1a; human myelocytic leukemia cells) were obtained from American Type Culture Collection (ATCC, Manassas, VA, USA). These cell lines are commonly used in research studies as experimental AML models (19)(20)(21). Primary human AML cells (de novo AML 6373, harboring FLT3-ITD mutation) were collected by leukapheresis from AML patients at the University Hospital, University of Pennsylvania, with informed consents (IRB protocol 703185).
K562-Luc cells were maintained in Roswell Park Memorial Institute (RPMI) 1640 media supplemented with 10% fetal bovine serum (FBS). To maintain luciferase-labeled cells, blasticidin antibiotic was added at a concentration of 8 μg/ml.
In our experiments, KG1a cells were cultured in RPMI 1640 media supplemented with 10% fetal bovine serum. Both K562-Luc and KG1a cells were grown in a humidified chamber with 5% CO 2 and 95% humidity at 37°C.
Fluorobenzyl polyethylene glycol mono-triazole tetraiodothyroacetic acid (fb-PMT) was synthesized at our facility (Pharmaceutical Research Institute, Rensselaer, NY, USA), and GMP scaleup was done at Dalton Pharmaceuticals (Toronto, Canada) (9,18). fb-PMT (molecular weight 2,478.9 Da) is a white powder that is soluble in Tris buffer at pH 8.0, 100 mg/ml, with a final pH of 7.4. Competitive Binding of fb-PMT to Purified avb3 The binding affinity of fb-PMT to purified avb3 was assessed using a previously described methods (9,22

Animals and Treatment Protocols
Animal studies were carried out at the Albany Stratton VA Medical Center (Albany, NY, USA) animal facility, and protocols were approved by the Institutional Animal Care and Use Committee (IACUC) (protocol number 545017). Eighty male NSG-S mice (6-8 weeks of age) were purchased from Jackson Laboratories (Bar Harbor, ME). Preconditioning was done by intraperitoneal injection of busulfan (30 mg/kg, Otsuka America Pharmaceutical Inc., Hayward, CA, USA) 24 h prior to cell injections. K562-Luc cells and primary AML cells (6373) (5-10 × 10 6 per mouse) were transplanted via tail vein injection into mice. For the K562-Luc animal model (40 mice), in vivo imaging system (IVIS) (Perkin Elmer, Waltham, MA, USA) scans and the peripheral blood smears examination were performed on animals once a week. The fb-PMT treatment schedule was initiated on day 10 post-implantation when increased counts of blast cells became evident in peripheral blood smears and confirmed by IVIS signals. fb-PMT was administered subcutaneously (s.c.) daily at three different doses (1, 3, and 10 mg/kg body weight) or vehicle, phosphate-buffered saline (PBS) (control) for 21 days for both the ON arm (21 days treatment and then 20 mice have been sacrificed) and the ON+OFF arm (21 days treatment followed by 14 days treatment discontinuation, and then, the remaining 20 mice have been sacrificed). Control animals were administered with vehicle (PBS, pH 7.4) daily.
In experiments using the primary AML cell animal model (40 mice), the treatment protocol was initiated on animals after confirmation of successful engraftment. Treatment was initiated on day 40 post-implantation with fb-PMT (1, 3, and 10 mg/kg) or control (vehicle, PBS) daily s.c. for 28 days. Twenty animals (ON arm) were humanely sacrificed after 28 days of treatment, and peripheral blood smears and bone marrow aspirates were examined histologically at the end of the 28 days of treatment.
To evaluate the relapse after treatment, the remaining 20 mice (ON + OFF arm) were maintained without treatment for an additional 14 days; then, they were humanely sacrificed and processed to obtain samples of peripheral blood smears, bone marrow aspirates, and organs for histological examination. Maintaining for 14 days (ON + OFF) was established based on the animals' condition in the control groups.

Assessment of Leukemic Cells Engraftment by Flow Cytometry and Immunohistostaining
Human AML engraftment was assessed by flow cytometry and defined as the percentage of human CD45+/CD33+ cells in total live mononuclear cells. Fresh bone marrow cells from NSG-S mice engrafted with K562-Luc and primary AML cells (6373) were collected at day 10 and 40 post-engraftment, respectively, once the blast cells were detected in peripheral blood smear. Samples were stained with antibodies for cell surface markers: anti-human CD45-PE and anti-human CD33-FITC (BD Biosciences, San Jose, CA, USA). Cells were incubated with monoclonal antibodies for 15 min at room temperature, washed once in PBS containing 0.1% human serum albumin (HSA), and analyzed by flow cytometry. Data acquisition was performed using a FACS Aria III (BD Biosciences) equipped with an argon and red diode laser, and analysis was performed using Cell Quest software (BD Biosciences).
As the K562-Luc cells express dim CD34, immunohistochemistry was performed for the formalin-fixed decalcified femurs from primary AML cells (6373) transplanted mice, paraffin-embedded and sectioned at 5-μm sections. Slides were stained using human anti-CD34 primary antibody (R&D System, Minneapolis, MN, USA), then with HRP-conjugated secondary antibody (Cell Signaling Technology Inc. Danvers, MA, USA). HRP activity was detected by diaminobenzidine tetrahydrochloride (DAB), and the slides were counterstained by methyl green.

RNA Isolation From AML Cells and Microarrays
K562-Luc and KG1a cells were cultured in 50-cm 2 cell culture flasks with 10 ml phenol red free RPMI media containing 10% fetal calf serum (FCS) to 75% confluence. K562-Luc and KG1a cells were treated (at 50% confluence) with 30 μM fb-PMT for 48 h. Total RNA was immediately isolated from harvested cells using Trizole and checked for quality using an Agilent Bioanalyzer (Agilent Technologies, Santa Clara, CA) before being used for microarray analysis. The quality and the concentrations of the extracted RNA were analyzed using a NanoDrop (Thermo Fisher Scientific, Waltham, MA) and the Agilent Bioanalyzer. RNA samples (100 ng) deemed to be of sufficient quality (RIN >8) were processed according to the standard Affymetrix RNA labeling protocol. At least two independent biological replicates of control and treated samples were concurrently interrogated in microarray analyses. In preliminary experiments, the treatment dose and duration were carefully selected so as to not significantly affect growth and survival of target cells for the duration of the experiments.

Microarray Analysis
Labeled RNA samples were processed for hybridization employing the Clariom ™ S human array platform (Affymetrix, Santa Clara, CA) at the Center for Functional Genomics, University at Albany, Rensselaer, NY. Briefly, 100 ng of total RNA was processed using the WT Plus Reagent kit (Affymetrix). Sense target complementary DNAs (cDNAs) were generated using the standard Affymetrix WT protocol and hybridized to Affymetrix Human Clariom S arrays. Arrays were washed, stained, and scanned on a GeneChip 3000 7G scanner using Affymetrix GeneChip Command Console Software (AGCC). Transcriptome Analysis Console Software (TAC v3.0.1.5) was used to identify differentially expressed genes (DEGs). Briefly, the CEL files were summarized using the SST-RMA algorithm in TAC, and the normalized data were subjected to one-way ANOVA with a Benjamini-Hochberg false discovery rate correction included (p < 0.05). A 1.5-fold expression change cutoff was used to select entities that were statistically differentially expressed between the conditions being compared (treated and untreated groups). In the standard workflow protocol, the fragmented biotin-labeled cDNAs were hybridized for 16 h to Affymetrix Arrays, scanned on an Affymetrix Scanner 3000 7G using AGCC software, and processed as described above. Alternatively, CEL files after QC screening using Affymetrix Expression Console software were imported into GeneSpring GX11.5 (Agilent Technologies). The data were then quantile normalized using PLIER and baseline transformed to the median of the control samples. The probe sets were further filtered to exclude the bottom 20th percentile across all samples. The resulting entity lists were subjected to an unpaired t-test with the Benjamini-Hochberg false discovery rate correction and a 1.5-fold expression changes filter to identify differentially expressed transcripts between the control and test conditions at a p <0.05. All analyzed and reported data are MIAME compliant, and the raw data have been deposited in Gene Expression Omnibus (GEO; GSE95790) as detailed on the Microarray Gene Expression Data Society (MGED) website (http://www.mged.org/Workgroups/ MIAME/miame.html). Overall, the workflow of the microarray analyses was modeled based on previously published contributions (23).
Gene set enrichment analyses of DEGs were done using the Enrichr bioinformatics platform, which enables the interrogation of nearly 200,000 gene sets from more than 100 gene set libraries. The Enrichr API (January 2018 through October 2020 releases) (24,25) was used to test genes of interest for significant enrichment in numerous functional categories. When technically and analytically feasible, different sets of DEGs defined at multiple significance levels of statistical metrics and comprising dozens to several thousand individual genetic loci were analyzed using differential gene set enrichment analysis (GSEA) to gain insights into biological effects of DEGs and infer potential mechanisms of anticancer activities. This approach was successfully implemented for the identification and characterization of human-specific regulatory networks governed by human-specific transcription factor-binding sites (26) and functional enhancer element (27): 13,824 genes associated with 59,732 human-specific regulatory sequences (28) and 8,405 genes associated with 35,074 human-specific neuroregulatory singlenucleotide changes (29). Initial GSEAs entail interrogations of each specific set of DEGs using 29 distinct genomic databases, including comprehensive pathway enrichment Gene Ontology (GO) analyses followed by in-depth analyses of the selected genomic databases deemed most statistically informative. In all tables and plots (unless stated otherwise), in addition to the nominal p-values and adjusted p-values, the "combined score" calculated by Enrichr software is reported, which is a product of the significance estimate and the magnitude of enrichment [combined score c = log (p) * z, where p is the Fisher's exact test p-value and z is the z-score deviation from the expected rank].

Statistical Analysis
An overall comparison of the means for all groups was carried out using a one-way ANOVA. Tukey confidence intervals were used to test for differences in means for each experimental group versus the control group. Results are presented as means ± SD. A value of p < 0.05 indicated a statistically significant difference.

In Vitro Binding Affinity of fb-PMT With the Thyrointegrin avb3
In binding affinity experiments of fb-PMT, we confirmed that fb-PMT has a high affinity for the thyrointegrin avb3 receptors with a lower IC 50 (50% inhibitory concentration) of 0.23 nM (Figure 1).

Preclinical In Vivo Therapy Experiments Revealed Potent fb-PMT Anticancer Activities
Effects of fb-PMT Therapy on K562-Luc Human Leukemic Cell Line and FLT3-ITD Primary Human AML Cells Engrafted in Transgenic Mice In the K562-Luc engrafted in transgenic mice, blast cells appeared in the blood smears of NSG-S mice 10 days after After termination, the bone marrow K562-Luc engrafted mice with a daily treatment of fb-PMT at 3 mg/kg manifested 30%-40% infiltration with blast cells, while 70% maturation could be detected. fb-PMT-treated animals at 10 mg/kg dose presented bone marrows with blast cell counts <5% and >95%; normal maturation have been documented (segmented neutrophils). The remission was maintained in all treated mice at least 2 weeks after fb-PMT therapy discontinuation ( Figures 3A, B; Supplementary Figure S2A).
IVIS scans and histopathological results at sacrifice showed a dose-dependent decrease in the brain, lung, liver, and spleen infiltration with the leukemic cells in the group of fb-PMTtreated mice (10 mg/kg) in comparison to control group (Supplementary Figures S3, S4). The fb-PMT therapy at 10 mg/kg dose in the ON + OFF treatment group resulted in successfully maintained remission in all animals 2 weeks after withdrawal of the daily treatment. The sustained remission was confirmed using blood smear analyses, IVIS scans, flow cytometry, and histopathological examinations.
Regarding the bone marrow samples from mice engrafted with primary AML cells (FLT3-ITD), the fb-PMT-treated group (10 mg/kg) restored the normal bone marrow maturation with abundant megakaryocytes in comparison to control animals ( Figures 3C, D). The results were confirmed with flow cytometry and immunohistochemistry analysis (Supplementary Figure S2).
Furthermore, we evaluated the splenic infiltration in our animal models. Histopathological results showed a marked decrease in splenic metastases of the leukemic cells in the group treated with fb-PMT (10 mg/kg) compared to control group (Supplementary Figure S5). Similarly, to the K562-Luc AML experiments, the primary AML model (ON + OFF) group (10 mg/kg) manifested the successful maintenance of remission 2 weeks after withdrawal of daily therapy. The splenic weight showed marked decrease (80%) even with the low dose (1 mg/ kg). The ON + OFF groups maintained normal splenic weight in comparison to control, which may reflect successful prevention of engraftment (Supplementary Figure S5A). Treatment with fb-PMT daily for 28 days (ON treatment) or 28 days ON and 14 days off treatment (ON + OFF treatment) resulted in maximal suppression of primary AML infiltration into the spleen of AMLengrafted transgenic mice (Supplementary Figure S5B).
Additionally, in our in vivo therapy experiments (fb-PMT), survival of the animals in the therapy group was 100% at the end of the treatment protocol. In the ON + OFF arm, all animals in the control group reached the moribund state (per definition of the experimental protocol approved by the IACUC) and must be humanly sacrificed. Thus, 100% of animals in the control group reached this terminal survival stage. Correspondingly, fatality rate in the control group was 100%, and survival rate in the therapy group was 100%. Finally, we did not notice any changes in mice weights in all treated groups in comparison to the control (untreated) (Supplementary Figure S6).  Table 1 identified a total of 25 genes, the differential expression of which appears to define molecular signals of either activation of or interference with transcriptional pathways in fb-PMTtreated human AML cells (Supplementary Figure S7). GSEA of genes comprising the 25-and 12-gene expression signatures validated their significance in defining observations of the molecular mimicry of transcriptional pathways' activation and interference induced by fb-PMT treatment in human AML cells ( Table 2; Supplementary Figures S7-S9). GSEA of all significant DEGs confirmed and extended these findings (Supplementary Table S1). Interestingly, GSEA identified the SNAI transcriptional pathway as the most significantly enriched pathway of the molecular interference observed in K562 cells treated with fb-PMT among either down-or upregulated DEGs (Supplementary Figure S10 and Supplementary Tables S1, S2). Additional examples of the specific genes and pathways of potential functional significance revealed by the GSEA of 233 genes downregulated in KG1a cells after fb-PMT treatment are shown in Table 3 and Supplementary Figure S9 and Supplementary  Table S3. Of note, GSEA of the LINCS L1000 Ligand Perturbations database of upregulated genes revealed evidence of molecular interference with functions of multiple growth factors in human cancer cell lines. estrogens with multiple kinases in human tissues. Integration of 16 estrogen-regulated genes with 35 genes encoding kinases engaged in regulatory crosstalk in human tissues generated the 50-gene signature of estrogen pathway/multi-kinase gene expression regulatory matrix, which appears engaged in the cell cycle progression pathway. Intriguingly, GSEA of the 50gene interference signature with estrogen-kinase regulatory matrix using the DisGeNET database of human disorders revealed that these genes were implicated in a remarkably broad spectrum of human malignancies (Supplementary Figure S11 and Supplementary Table S3).

DISCUSSION
The present study assessed the efficacy of a novel thyrointegrin avb3 antagonist (fb-PMT) against human AML cells. fb-PMT proved to be a highly effective anticancer agent in vivo.  Experiments using different human AML models in mice documented eradication of the leukemic cells' engraftment after 3-4 weeks of continuous treatment with fb-PMT. Experimental therapy ON + OFF studies showed the significant efficacy of fb-PMT in preventing relapse, thus confirming the curative effects in vivo of fb-PMT treatment in clinically relevant animal models of human AML. The role of integrin in leukemogenesis was indicated by Yi et al., who reported that binding of leukemia cells to the bone marrow extracellular matrix (ECM) through integrins might influence drug response and the survival of leukemic cells (11). Integrin aVb3 has been reported to be more expressed in AML cells especially CD34-positive cells, monocytic leukemias, patient with NPM, and FLT3-ITD (14). Consistent with the previous reports on mechanisms of anticancer actions of thyrointegrin avb3 antagonists (30-35), genome-wide microarray screens reported here demonstrated that fb-PMT appears to exert its potent anticancer actions on human AML cells through the molecular interference mechanism with multiple signaling pathways supporting growth and survival of leukemic cells. We detected significant molecular signals of transcriptional interference with gene expression induced in human cancer cells in response to multiple growth factors such as epidermal growth factor (EGF), insulin-like growth factor-1 (IGF-1), transforming growth factor alpha (TGFA), and many others.
SNAI expression was a common target for both fb-PMTtreated cells (K562 and KG1 cells). The overexpression of SNAI1 in leukemic cells is the key modulator of epithelial-tomesenchymal transition (EMT), which have recently emerged as new players in the leukemogenesis. SNAI expression contributes to impaired differentiation and proliferation of leukemic cells. The effect of Snai1 has been reported to be mediated by interaction with the histone demethylase (LSD1; lysine-specific histone demethylase1), which modifies different gene expression (49,50).
Finally, consistent with our previous reports on the crosstalk between integrin avb3 and estrogen receptor a (ERa), which contributes to the induced proliferation of cancer cells (55)(56)(57)(58), we found that fb-PMT interfered with estrogen signaling in human AML cells. The avb3 agonist (thyroid hormone) was associated with increased phosphorylation and nuclear enrichment of Era (55). Hsiesh's group reported that both T4 and estradiol (E2) caused nuclear translocation of integrin av and phosphorylation of Era in ovarian cancer cell line (SKOV-3). They successfully decreased the cell proliferation (by more than 60%) using specific ERa antagonist (ICI 182,780; fulvestrant), which blocks T4-induced ERK1/2 activation, ERa phosphorylation, proliferating cell nuclear antigen (PCNA) expression, and proliferation (55).
fb-PMT is an effective anticancer agent against solid tumors and hematological malignancies, with broad spectrum, potent anti-angiogenic activity against all known growth factors and other pro-angiogenesis stimuli (9,59,(60)(61)(62). Collectively, preclinical findings of fb-PMT warrant its clinical investigation for the effective and safe management of AML.

CONCLUSION
Our novel thyrointegrin avb3 antagonist, fb-PMT, represent a potential clinical candidate supported by its efficacy against human xenograft models of AML. Our genomic data demonstrated the potent anticancer actions on human AML through the molecular interference mechanism with multiple signaling pathways supporting growth and survival of leukemic cells. fb-PMT could have a broader application because it could be utilized, either alone or in combination with chemotherapeutic agents, to treat AML or other cancers.

DATA AVAILABILITY STATEMENT
The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found below: https://www.ncbi. nlm.nih.gov/genbank/, GSE183772.

AUTHOR CONTRIBUTIONS
SM designed the experiment and is the principal investigator. ND and ST conducted the experiment. ND did the data analysis. GG performed genomics and bioinformatics analyses, contributed to data interpretation and manuscript writing. ND contributed to the manuscript writeup and data interpretation. All authors contributed to the article and approved the submitted version.

ACKNOWLEDGMENTS
Special thanks to Dr. Sridar V. Chittur, Center for Functional Genomics, SUNY Albany, for the processing microarray samples.