Association Of Expression Levels Research Articles

PD-L1 immunohistochemistry assay optimization to provide more comprehensive pathological information in classic Hodgkin lymphoma

Overexpression of PD-L1 can be a predictive marker for anti-PD-1 therapeutic efficacy in classic Hodgkin lymphoma (CHL); however, harmonization of different IHC assays remains to be accomplished, and interpretations of PD-L1 immunostaining results remain controversial in CHL. In this study, we sought to optimize the PD-L1 immunohistochemistry (IHC) assay in CHL. All tests were performed on a tumour tissue microarray established from 54 CHL cases. Three IHC antibodies (405.9A11, SP142, 22C3) for detecting PD-L1 expression were compared semi quantitatively with the RNAscope assay (No. 310035, ACD), and the difference in the expression in background immune cells (ICs) between assays and the associations of expression levels with densities of TILs/TAMs were also analysed. 405.9A11 demonstrated best specificity in HRS cells and best sensitivity in ICs. Positive expression of PD-L1 was more frequent in ICs (85.2%) than in HRS cells (48.1%). Different subgroups of background ICs, including tumour-associated macrophages (TAMs), were assessed and scored for CD4, CD8, FOXP3, and CD163 expression. PD-L1 expression on ICs was the factor most associated with the density of TAMs. 405.9A11 provided the most convincing PD-L1 expression results. Pathologists should report PD-L1 expression in a combined manner, including both the status of HRS cells and the percentage of PD-L1-positive ICs.

Bioinformatic analysis of genetic changes CLOCK, BMAL1, CRY1, CRY2, PER1, PER2, PER3, and NPAS2 proteins in HCC patients.

Genes related to the circadian rhythm control various biological processes. The aim of this study was to comprehensively investigate the mutational and mRNA profile of core circadian rhythm genes in hepatocellular cancer (HCC) samples. In this study, the gene profile of a total of 369 patients with HCC was examined over the data obtained from the cancer genome atlas database through-cBioPortal. The effects of mutations on protein were examined by scoring the Polymorphism Phenotyping v2, Mutation Assessor, and SIFT-databases. While the association of genes with other genes was determined with the GeneMANIA-database, the association of expression levels in the genes with overall survival (OS) was evaluated with the Kaplan-Meier Plot database. As a result of the analyses, there were a total of 25 mutations. Decreased expression levels of PER1 (1.3e-05), PER3 (p=0.046), and CRY2 (p=1.8e-06) genes were found statistically associated with shorter OS. It was also found that increased expression levels of the PER2 (p=0.045) gene were associated with longer OS, and increased expression levels of the NPAS2 (p=9e-04) gene were associated with shorter OS. In particular, changes in the PER1, PER2, CRY2, and NPAS2 genes may provide possible molecular targets in chemotherapy and immunotherapy for HCC patients.

Seasonal and sexual variation in mRNA expression of selected adipokine genes affecting fat deposition and metabolism of the emu (Dromaius novaehollandiae)

Emus are farmed for fat production. Oil rendered from their back and abdominal fat pads has good anti-oxidant and anti-inflammatory properties and has ingredients that promote cell growth. Our objective is to examine the mRNA expression of 7 emu adipokine genes (eFABP4, eSCD1, eAdipoQ, eAdipoR1, eAdipoR2, eLEP and eLepR) to identify gene markers that may help improve emu fat production. Back and abdominal fat tissues from 11 adult emus were biopsied at four time points (April, June, August and November). Total RNA was isolated and cDNA was synthesized. Gene specific primers were designed for partial cloning fragments to amplify the open reading frame of the 7 genes. eLEP was not expressed in emu fat tissue. Nucleotides and amino acids sequences of the 6 expressed gene were compared with homologs from other species and phylogenetic relationships established. Seasonal mRNA expression of each gene was assessed by quantitative RT-PCR and differential expression analysed by the 2−ΔΔCT method. The 6 expressed genes showed seasonal variation in expression and showed association of expression level with back fat adiposity. More whole-genome scanning studies are needed to develop novel molecular markers that can be applied to improve fat production in emus.

Differential expression of cancer associated plasma miRNAs in the ordnance factory workers, exposed to 2,4,6-Trinitrotoluene.

Objectives:To determine differential expression of microRNAs (miRNAs) in plasma of 2, 4, 6-Trinitrotoluene (TNT) exposed ordnance factory workers.Methods:A case control study was conducted at the Department of Toxicology, Armed Forces Institute of Pathology, Rawalpindi from July to December 2020. A total 30 subjects were recruited from an ordnance factory that were directly exposed to TNT and 120 non-exposed individuals from non-factory healthy population. Plasma levels of five miRNAs including miRNA-let-7a-2, miRNA-34a-1, miRNA-21-2, miRNA-106b-1, miRNA-122a-1 were measured by quantitative real-time polymerase chain reaction (RT-PCR).Results:Micro RNAs showed a wide range of Ct (cycle threshold) values ranging from 23.48 to 41.94. Among the five miRNAs let-7a-2 and miRNA-122a-1 displayed relatively high expression with Ct values ranging from 26.58 ± 2.25 to 27.18 ± 0.80 respectively. Relative fold change expression for all five miRNAs of exposed individuals were found high (p <0.0001) vs non-exposed. Dividing fold change expression of exposed individuals into two groups as ≤ 10 and > 10, the individuals having ≤ 10-fold change expression were19 (63.3%) in miRNA-let-7a-2, 30 (100%) in miRNA-34a-1 and 23 (76.7%) in miRNA-122a-1 while in miRNA-21-2 and miR-106b-1, 23 (76.7%) and 18(60%) individuals had > 10-fold change expression respectively. Among the five miRNAs in exposed individuals, miRNA-let-7a-2, miR-21-2, miR-106b-1 and miR-122a-1 were found highly expressed with fold change expression > 10 (p <0.0001). No significant association was found between miRNAs expression levels with age and working duration.Conclusion:The study shows upregulation of all five miRNAs in TNT exposed subjects with no significant association of expression levels with age and working duration.

Altered expression profile of BAFF receptors on peripheral blood B lymphocytes in Graves\u2019 disease

BackgroundB lymphocyte activating factor (BAFF) is a growth factor regulating B lymphocytes survival and maturation. Serum BAFF levels were elevated in patients affected with autoimmune thyroid diseases (AITD), including Graves’ disease (GD) and Hashimoto’s thyroiditis (HT). The aim of this study is to explore the association of expression levels of BAFF and its receptors with AITD.MethodsFifty-two GD patients, 39 Hashimoto’s thyroiditis (HT) patients and 23 healthy controls (HC) were recruited in this study. Serum BAFF levels were measured by ELISA. Expression of BAFF receptors, including BAFF receptor 3 (BR3) and transmembrane activator and calcium-modulating and cyclophilin ligand interactor (TACI), on B lymphocytes were analyzed by flowcytometry. Effects of steroids on serum BAFF levels and expression of BR3 and TACI were also observed in 10 patients with Graves’ orbitopathy (GO) receiving steroids therapy.ResultsSerum BAFF levels were significantly elevated from 0.93 ± 0.24 ng/ml in HC to 1.18 ± 0.33 ng/ml in GD (P = 0.0027) and 1.02 ± 0.24 ng/ml in HT (P = 0.0331). BR3 expression on peripheral B lymphocytes were elevated in GD (mean MFI: 4.52 ± 2.06 in GD vs. 3.00 ± 0.87 in HC, P = 0.0015), while TACI expression on peripheral B lymphocytes were decreased in GD without significance (mean MFI: 7.96 ± 4.06 in GD vs. 9.10 ± 3.37 in HC, P = 0.1285). Expression of BR3 and TACI was not changed significantly in HT patients. Steroids significantly suppressed serum BAFF concentrations (from 1.18 ± 0.27 ng/ml to 0.97 ± 0.10 ng/ml, P = 0.0364) and BR3 expression in GO patients (mean MFI from 6.26 ± 4.91 to 4.05 ± 1.58, P = 0.0083).ConclusionsAltered expression of BAFF and its receptor may mediate the autoimmunity in GD. Restoring the normal expression profile of receptors for BAFF could be a new strategy to treat GD.

Abstract 3709: miR-21-3p: A potential oncomir in breast cancer

Abstract MIR21 is a well known oncomir in many cancer types including breast cancer. Most studies that have described the oncogenic properties of MIR21 have focused on the leading strand miR-21-5p. Fewer studies have focused on the passenger strand miR-21-3p, but in a few types of cancer it has been shown to have oncogenic properties. A handful of studies suggest that miR-21-3p could be a biomarker in breast cancer. MIR21 is located at 17q23.1, a region which is often amplified in breast tumors. It overlaps the 3´ end of VMP1 but it has its own distinct promoter. The aim of this study was to analyze whether miR-21-3p associated with prognostic factors in breast cancer. The levels of miR-21-5p and miR-21-3p were measured by qPCR in 144 breast tumors from a cohort of breast cancer patients (cohort 1). The association of expression levels with clinical and pathological factors was analyzed by Student´s t-test and Anova, and with survival by Kaplan-Meier, the log-rank test, and the Cox proportional hazards test. To confirm the results, available data were used from breast cancer cohorts from The Cancer Genome Atlas (TCGA) (n=256) and METABRIC (n=1286). The mean expression levels of miR-21-5p were significantly higher than those of miR-21-3p in breast tumors from cohort 1 (p=2.2e−10). However, only miR-21-3p was more highly expressed in tumors than normal breast tissue (p=0.003), and in all three cohorts there was a strong positive correlation between MIR21 copy number and miR-21-3p expression levels. There was a significant higher expression of miR-21-3p in HER2 positive tumors compared to HER2 negative tumors in the two larger cohorts (p &amp;lt; 0.05), and high miR-21-3p levels associated with higher histograde in the largest cohort (9.2e−14). A shorter breast cancer specific survival was associated with higher miR-21-3p expression in the METABRIC cohort (HR 1.338, CI 1.104-1.622, p=0.003). HER2 was the largest confounding factor but even after adjustment for HER2 positivity the effect remained significant (HR 1.260, CI 1.036-1.532, p = 0.021). Our data show that miR-21-3p is expressed in breast tissue and tumors. Furthermore, our preliminary data suggest that miR-21-3p may be an indicator of worse outcome for breast cancer patients. However, additional work is needed to elucidate the association of miR-21-3p expression with distinct prognostic factors in breast cancer. Citation Format: Arsalan Amirfallah, Adalgeir Arason, Bjarni A. Agnarsson, Oskar Th Johannsson, Bylgja Hilmarsdottir, Rosa Bjork Barkardottir, Inga Reynisdottir. miR-21-3p: A potential oncomir in breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3709.

Mining the role of angiopoietin-like protein family in gastric cancer and seeking potential therapeutic targets by integrative bioinformatics analysis.

BackgroundThe indistinctive effects of antiangiogenesis agents in gastric cancer (GC) can be attributed to multifaceted gene dysregulation associated with angiogenesis. Angiopoietin‐like (ANGPTL) proteins are secreted proteins regulating angiogenesis. They are also involved in inflammation and metabolism. Emerging evidences have revealed their various roles in carcinogenesis and metastasis development. However, the mRNA expression profiles, prognostic values, and biological functions of ANGPTL proteins in GC are still elucidated.MethodsWe compared the transcriptional expression levels of ANGPTL proteins between GC and normal gastric tissues using ONCOMINE and TCGA‐STAD. The prognostic values were evaluated by LinkedOmics and Kaplan–Meier Plotter, while the association of expression levels with clinicopathological features was generated through cBioPortal. We conducted the functional enrichment analysis with Metascape.ResultsThe expression of ANGPTL1/3/6 was lower in GC tissues than in normal gastric tissues. High expression of ANGPTL1/2/4 was correlated with short overall survival and post‐progression survival in GC patients. Upregulated ANGPTL1/2 was correlated with higher histological grade, non‐intestinal Lauren classification, and advanced T stage, while ANGPTL4 exhibited high expression in early T stage, M1 stage, and non‐intestinal Lauren classification.ConclusionsIntegrative bioinformatics analysis suggests that ANGPTL1/2/4 may be potential therapeutic targets in GC patients. Among them, ANGPTL2 acts as a GC promoter, while ANGPTL1/4’s role in GC is still uncertain.

Altered Expression of Circulating miR-377 and miR-98 in Relapsing-remitting Multiple Sclerosis

Background and Aims: Multiple sclerosis (MS) has been assumed to be a Complex and indecipherable disease, and poorly understood with regard to etiology which is characterized by relapses and remissions. The expression of microRNAs (miRNAs) is known to be associated with the regulation of immune responses. Recently, investigations have reported that miRNA expression profiles in blood cells become changed in MS. The aim of this study was to elucidate the alterations in the expression of circulating miR377 and miR-98 in 60 relapsing-remitting MS (RRMS) patients in comparison with controls. Materials and Methods: This study was conducted using a quantitative real-time polymerase chain reaction method to explore the expression of circulating miR-377 and miR-98 in peripheral blood mononuclear cells from 60 RRMS patients, 30 of whom were recurring patients, 30 were two months after relapse patients, and 30 others were controls, in order to examine the association of expression level of these miRNAs with RRMS. Results: Results indicated that the expression of miR-377 significantly increases in recurring patients and two months after relapse patients in comparison with controls (p=0.0017 and p=0.0001, respectively). However, miR-98 demonstrated down regulation in recurring patients and two months after relapse patients (p=0.0002 and p=0.0001, respectively). Conclusions: It can be concluded that miR-377 and miR-98 may be prospective biomarkers with the potential use for diagnosis of RRMS patients in the future investigations.

Association of Expression Levels or Activation Status of STAT3 with Treatment Outcomes of Sunitinib in Patients with Renal Cell Carcinoma.

The expression level of signal transducer and activator of transcription 3 (STAT3) in tumor cells is reported to associate with response to therapy and with survival time in various types of cancer. This retrospective study aimed to elucidate the association of STAT3 expression in tumor cells with the therapeutic outcomes of sunitinib in patients with renal cell carcinoma (RCC). Patients with metastatic RCC who received sunitinib therapy were enrolled in this study. All patients underwent nephrectomy for RCC, and nephrectomy specimens were stained for STAT3 and phosphorylated STAT3 (p-STAT3) by immunohistochemistry. We assessed 51 patients receiving sunitinib as a first-line therapy. STAT3 expression levels did not influence progression-free survival (PFS) and overall survival (OS); however, patients with p-STAT3-positive tumors exhibited significantly worse PFS compared with those with p-STAT3-negative tumors (log-rank test, P = 0.034). OS tended to be prolonged in patients with p-STAT3-negative tumors. Objective response rate or disease control rate based on the best overall response did not show a significant association with STAT3 or p-STAT3 expression. Univariate Cox proportional hazard regression analyses for clinical predictors revealed that p-STAT3 positivity significantly correlated with shorter PFS (hazard ratio [HR], 2.22, P = 0.041), whereas p-STAT3 expression was not related to the OS. Activated STAT3 in tumor tissues shows a significant association with poor prognosis in patients with RCC who received sunitinib as a first-line therapy, and positive p-STAT3 expression could be a potential biomarker for refractoriness to sunitinib therapy.

Abstract P6-07-22: Association of Hedgehog signaling pathway with luminal B sub-type of breast cancer affected patients of Pakistan

Abstract Introduction Hedgehog pathway dysregulation is observed in different types of cancers including breast. In the present study, expression profiles of hedgehog pathway molecules in breast cancer cohort of Pakistan and their probable association with molecular sub-types were explored. Methods The study was preceded with ethical approval and informed consent from respective institutions and participants. During 2013-2015, a total of 150 cancer biopsies along with adjacent normal tissues were prospectively collected immediately after surgery and processed for RNA isolation. Transcriptional profiles of salient members including SHH, DHH, IHH, PTCH-1, SMO and GLI-1 were quantified using qRT-PCR. Cohort was categorized into molecular sub-types following St. Gallen International Expert Consensus System. Association of expression levels of these aforementioned molecules with various clinico-pathological parameters was explored. Result Both SHH (p=0.01) and DHH (p&amp;lt;0.001) showed elevated expression among tumors in comparison to their controls. Similarly, PTCH-1 (p&amp;lt;0.001) and GLI-1 (p=0.002) were also significantly up regulated in the cohort. Interestingly, strong positive correlations were observed among the pathway molecules (r-value ranging from 0.45 to 0.81) which highlight their interdependence towards tumor progression. A significant correlation of SHH, DHH, PTCH-1 and GLI-1 was observed with advanced tumor sizes, stages, grades and nodal involvement (p&amp;lt;0.05). Association of IHH, SMO and GLI-1 over expression with cancer metastasis was also established in the cohort. SHH, PTCH-1 and GLI-1 were significantly linked with laterality, age and menopausal status. Expression of SHH (p=0.002) was more related to younger age group (mean age &amp;lt; 45 yrs) patients in comparison to elderly women. Moreover all hedgehog molecules were strongly related to hormonal receptors (ER and PR) (r-value ranging from 0.51 to 0.86) while over-expression of HER-2 was not associated with any pathway component. Briefly, 53% (79) of the cohort was categorized as Luminal-B, 18% (27) triple negative, 15% (23) Luminal-A and 14% (21) HER-2 for sub-typing of breast cancer patients in the cohort. Expression of SHH was significantly associated with the molecular sub-types (p=0.02) and age (p=0.005) using Pearson Chi-Square test. Elevated expression of SHH was observed in 60% of the patients in Luminal B sub-type. Conclusion Hedgehog pathway plays a crucial role in breast cancer progression and is found to be activated in Luminal B sub-type in this cohort. As Luminal B is a more aggressive type of breast cancer having poor prognosis and early-onset, association of SHH with Luminal-B and younger age patients signify it importance as a biomarker for early diagnosis of young patient's. Hence therapeutic interventions for hedgehog pathway can improve the prognosis of patients categorized as Luminal B subtype of breast carcinogenesis. Citation Format: Riaz SK, Rashid R, Shah STA, Wang F, Malik MFA. Association of Hedgehog signaling pathway with luminal B sub-type of breast cancer affected patients of Pakistan [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-07-22.

Association of expression levels in skeletal muscle and a SNP in the MYBPC1 gene with growth-related trait in Japanese Black beef cattle.

Association of expression levels in skeletal muscle and a SNP in the MYBPC1 gene with growth-related trait in Japanese Black beef cattle.

Genome-Wide Gene Expression Profiles in Antioxidant Pathways and Their Potential Sex Differences and Connections to Vitamin C in Mice

Vitamin C (VC) is well known as an antioxidant in humans, primates and guinea pigs. Studies have suggested gender differences in VC requirements in humans, and gender differences in oxidant injury vulnerability in early life may represent a biological mechanism contributing to gender disparity in later life. Using spontaneous bone fracture (sfx) mice, which lack the gene for L-Gulonolactone oxidase (Gulo), we studied the potential sex difference in expression profiles of oxidative genes at the whole-genome level. Then, we analyzed data of gene expressions in a mouse population of recombinant inbred (RI) strains originally derived by crossing C57BL/6J (B6) and DBA/2J (D2) mice. Our data indicated that there were sex differences in the regulation of pre- and pro-oxidative genes in sfx mice. The associations of expression levels among Gulo, its partner genes and oxidative genes in the BXD (B6 × D2) RI strains showed a sex difference. Transcriptome mapping suggests that Gulo was regulated differently between female and male mice in BXD RI strains. Our study indicates the importance of investigating sex differences in Gulo and its oxidative function by using available mouse models.

Identification of expression QTL (eQTL) of genes expressed in porcine M. longissimus dorsi and associated with meat quality traits

BackgroundGenetic analysis of transcriptional profiles is a promising approach for identifying and dissecting the genetics of complex traits like meat performance. Accordingly, expression levels obtained by microarray analysis were taken as phenotypes in a linkage analysis to map eQTL. Moreover, expression levels were correlated with traits related to meat quality and principle components with high loadings of these traits. By using an up-to-date annotation and localization of the respective probe-sets, the integration of eQTL mapping data and information of trait correlated expression finally served to point to candidate genes for meat quality traits.ResultsGenome-wide transcriptional profiles of M. longissimus dorsi RNAs samples of 74 F2 animals of a pig resource population revealed 11,457 probe-sets representing genes expressed in the muscle. Linkage analysis of expression levels of these probe-sets provided 9,180 eQTL at the suggestive significance threshold of LOD > 2. We mapped 653 eQTL on the same chromosome as the corresponding gene and these were designated as 'putative cis-eQTL'. In order to link eQTL to the traits of interest, probe-sets were addressed with relative transcript abundances that showed correlation with meat quality traits at p ≤ 0.05. Out of the 653 'putative cis-eQTL', 262 transcripts were correlated with at least one meat quality trait. Furthermore, association of expression levels with composite traits with high loadings for meat quality traits generated by principle component analysis were taken into account leading to a list of 85 genes exhibiting cis-eQTL and trait dependent expression.ConclusionHolistic expression profiling was integrated with QTL analysis for meat quality traits. Correlations between transcript abundance and meat quality traits, combined with genetic positional information of eQTL allowed us to prioritise candidate genes for further study.

Placental biomarkers of phthalate effects on mRNA transcription: application in epidemiologic research

BackgroundCYP19 and PPARγ are two genes expressed in the placental trophoblast that are important to placental function and are disrupted by phthalate exposure in other cell types. Measurement of the mRNA of these two genes in human placental tissue by quantitative real-time polymerase chain reaction (qPCR) offers a source of potential biomarkers for use in epidemiologic research. We report on methodologic challenges to be considered in study design.MethodsWe anonymously collected 10 full-term placentas and, for each, sampled placental villi at 12 sites in the chorionic plate representing the inner (closer to the cord insertion site) and outer regions. Each sample was analyzed for the expression of two candidate genes, aromatase (CYP19) and peroxisome proliferator activated receptor protein gamma (PPARγ) and three potential internal controls: cyclophilin (CYC), 18S rRNA (18S), and total RNA. Between and within placenta variability was estimated using variance component analysis. Associations of expression levels with sampling characteristics were estimated using mixed effects models.ResultsWe identified large within-placenta variability in both transcripts (>90% of total variance) that was minimized to <20% of total variance by using 18S as an internal control and by modelling the means by inner and outer regions. 18S rRNA was the most appropriate internal control based on within and between placenta variability estimates and low correlations of 18S mRNA with target gene mRNA. Gene expression did not differ significantly by delivery method. We observed decreases in the expression of both transcripts over the 25 minute period after delivery (CYP19 p-value for trend = 0.009 and PPARγ (p-value for trend = 0.002). Using histologic methods, we confirmed that our samples were comprised predominantly of villous tissue of the fetal placenta with minimal contamination of maternally derived cell types.ConclusionqPCR-derived biomarkers of placental CYP19 and PPARγ gene expression show high within-placental variability. Sampling scheme, selection of an appropriate internal control and the timing of sample collection relative to delivery can be optimized to minimize within-placenta and other sources of underlying, non-etiologic variability.

Ankyrin Repeat Domain 1, ANKRD1, a Novel Determinant of Cisplatin Sensitivity Expressed in Ovarian Cancer

The standard of care for ovarian cancer includes platinum-based chemotherapy. It is not possible, however, to predict clinical platinum sensitivity or to design rational strategies to overcome resistance. We used a novel approach to identify altered gene expression associated with high sensitivity to cisplatin, to define novel targets to sensitize tumor cells to platins and ultimately improve the effectiveness of this widely used class of chemotherapeutics. Using differential display PCR, we identified genes differentially expressed in a mutagenized cell line with unusual sensitivity to cisplatin. The most highly differentially expressed gene was selected, and its role in determining cisplatin sensitivity was validated by gene transfection and small interfering RNA (siRNA) approaches, by association of expression levels with cisplatin sensitivity in cell lines, and by association of tumor expression levels with survival in a retrospective cohort of 71 patients with serous ovarian adenocarcinoma. The most highly differently expressed gene identified was ANKRD1, ankyrin repeat domain 1 (cardiac muscle). ANKRD1 mRNA levels were correlated with platinum sensitivity in cell lines, and most significantly, decreasing ANKRD1 using siRNA increased cisplatin sensitivity >2-fold. ANKRD1 was expressed in the majority of ovarian adenocarcinomas tested (62/71, 87%), and higher tumor levels of ANKRD1 were found in patients with worse outcome (overall survival, P=0.013). These findings suggest that ANKRD1, a gene not previously associated with ovarian cancer or with response to chemotherapy, is associated with treatment outcome, and decreasing ANKRD1 expression, or function, is a potential strategy to sensitize tumors to platinum-based drugs.