Browsing by Author "Wang, Tao"
Now showing 1 - 10 of 14
Results Per Page
Sort Options
Item A Multiparameter Molecular Classifier to Predict Response to Neoadjuvant Lapatinib plus Trastuzumab without Chemotherapy in HER2+ Breast Cancer(American Association for Cancer Research, 2023) Veeraraghavan, Jamunarani; Gutierrez, Carolina; De Angelis, Carmine; Davis, Robert; Wang, Tao; Pascual, Tomas; Selenica, Pier; Sanchez, Katherine; Nitta, Hiroaki; Kapadia, Monesh; Pavlick, Anne C.; Galvan, Patricia; Rexer, Brent; Forero-Torres, Andres; Nanda, Rita; Storniolo, Anna M.; Krop, Ian E.; Goetz, Matthew P.; Nangia, Julie R.; Wolff, Antonio C.; Weigelt, Britta; Reis-Filho, Jorge S.; Hilsenbeck, Susan G.; Prat, Aleix; Osborne, C. Kent; Schiff, Rachel; Rimawi, Mothaffar F.; Medicine, School of MedicinePurpose: Clinical trials reported 25% to 30% pathologic complete response (pCR) rates in HER2+ patients with breast cancer treated with anti-HER2 therapies without chemotherapy. We hypothesize that a multiparameter classifier can identify patients with HER2-"addicted" tumors who may benefit from a chemotherapy-sparing strategy. Experimental design: Baseline HER2+ breast cancer specimens from the TBCRC023 and PAMELA trials, which included neoadjuvant treatment with lapatinib and trastuzumab, were used. In the case of estrogen receptor-positive (ER+) tumors, endocrine therapy was also administered. HER2 protein and gene amplification (ratio), HER2-enriched (HER2-E), and PIK3CA mutation status were assessed by dual gene protein assay (GPA), research-based PAM50, and targeted DNA-sequencing. GPA cutoffs and classifier of response were constructed in TBCRC023 using a decision tree algorithm, then validated in PAMELA. Results: In TBCRC023, 72 breast cancer specimens had GPA, PAM50, and sequencing data, of which 15 had pCR. Recursive partitioning identified cutoffs of HER2 ratio ≥ 4.6 and %3+ IHC staining ≥ 97.5%. With PAM50 and sequencing data, the model added HER2-E and PIK3CA wild-type (WT). For clinical implementation, the classifier was locked as HER2 ratio ≥ 4.5, %3+ IHC staining ≥ 90%, and PIK3CA-WT and HER2-E, yielding 55% and 94% positive (PPV) and negative (NPV) predictive values, respectively. Independent validation using 44 PAMELA cases with all three biomarkers yielded 47% PPV and 82% NPV. Importantly, our classifier's high NPV signifies its strength in accurately identifying patients who may not be good candidates for treatment deescalation. Conclusions: Our multiparameter classifier differentially identifies patients who may benefit from HER2-targeted therapy alone from those who need chemotherapy and predicts pCR to anti-HER2 therapy alone comparable with chemotherapy plus dual anti-HER2 therapy in unselected patients.Item AZI23'UTR Is a New SLC6A3 Downregulator Associated with an Epistatic Protection Against Substance Use Disorders(Springer Nature, 2018-07) Liu, Kefu; Yu, Jinlong; Zhao, Juan; Zhou, Yanhong; Xiong, Nian; Xu, Jie; Wang, Tao; Bell, Richard L.; Qing, Hong; Lin, Zhicheng; Psychiatry, School of MedicineRegulated activity of SLC6A3, which encodes the human dopamine transporter (DAT), contributes to diseases such as substance abuse disorders (SUDs); however, the exact transcription mechanism remains poorly understood. Here, we used a common genetic variant of the gene, intron 1 DNP1B sequence, as bait to screen and clone a new transcriptional activity, AZI23'UTR, for SLC6A3. AZI23'UTR is a 3' untranslated region (3'UTR) of the human 5-Azacytidine Induced 2 gene (AZI2) but appeared to be transcribed independently of AZI2. Found to be present in both human cell nuclei and dopamine neurons, this RNA was shown to downregulate promoter activity through a variant-dependent mechanism in vitro. Both reduced RNA density ratio of AZI23'UTR/AZI2 and increased DAT mRNA levels were found in ethanol-naive alcohol-preferring rats. Secondary analysis of dbGaP GWAS datasets (Genome-Wide Association Studies based on the database of Genotypes and Phenotypes) revealed significant interactions between regions upstream of AZI23'UTR and SLC6A3 in SUDs. Jointly, our data suggest that AZI23'UTR confers variant-dependent transcriptional regulation of SLC6A3, a potential risk factor for SUDs.Item CCL2/CCR2 signaling elicits itch- and pain-like behavior in a murine model of allergic contact dermatitis(Elsevier, 2019) Jiang, Haowu; Cui, Huan; Wang, Tao; Shimada, Steven G.; Sun, Rui; Tan, Zhiyong; Ma, Chao; LaMotte, Robert H.; Pharmacology and Toxicology, School of MedicineSpontaneous itch and pain are the most common symptoms in various skin diseases, including allergic contact dermatitis (ACD). The chemokine (C-C motif) ligand 2 (CCL2, also referred to as monocyte chemoattractant protein 1 (MCP-1)) and its receptor CCR2 are involved in the pathophysiology of ACD, but little is known of the role of CCL2/CCR2 for the itch- and pain-behaviors accompanying the murine model of this disorder, termed contact hypersensitivity (CHS). C57BL/6 mice previously sensitized to the hapten, squaric acid dibutyl ester, applied to the abdomen were subsequently challenged twice with the hapten delivered to either the cheek or to the hairy skin of the hind paw resulting in CHS at that site. By 24 h after the 2nd challenge to the hind paw CCL2 and CCR2 mRNA, protein, and signaling activity were upregulated in the dorsal root ganglion (DRG). Calcium imaging and whole-cell current-clamp recordings revealed that CCL2 directly acted on its neuronal receptor, CCR2 to activate a subset of small-diameter, nociceptive-like DRG neurons retrogradely labeled from the CHS site. Intradermal injection of CCL2 into the site of CHS on the cheek evoked site-directed itch- and pain-like behaviors which could be attenuated by prior delivery of an antagonist of CCR2. In contrast, CCL2 failed to elicit either type of behavior in control mice. Results are consistent with the hypothesis that CHS upregulates CCL2/CCR2 signaling in a subpopulation of cutaneous small diameter DRG neurons and that CCL2 can activate these neurons through neuronal CCR2 to elicit itch- and pain-behavior. Targeting the CCL2/CCR2 signaling might be beneficial for the treatment of the itch and pain sensations accompanying ACD in humans.Item Composite GRFS and CRFS Outcomes After Adult Alternative Donor HCT(American Society of Clinical Oncology, 2020-06-20) Mehta, Rohtesh S.; Holtan, Shernan G.; Wang, Tao; Hemmer, Michael T.; Spellman, Stephen R.; Arora, Mukta; Couriel, Daniel R.; Alousi, Amin M.; Pidala, Joseph; Abdel-Azim, Hisham; Agrawal, Vaibhav; Ahmed, Ibrahim A.; Al-Homsi, Samer; Aljurf, Mahmoud; Antin, Joseph H.; Askar, Medhat; Auletta, Jeffery J.; Bhatt, Vijaya Raj; Chee, Lynette; Chhabra, Saurabh; Daly, Andrew; DeFilipp, Zachariah; Gajewski, James; Gale, Robert Peter; Gergis, Usama; Hematti, Peiman; Hildebrandt, Gerhard C.; Hogan, William J.; Inamoto, Yoshihiro; Martino, Rodrigo; Majhail, Navneet S.; Marks, David I.; Nishihori, Taiga; Olsson, Richard F.; Pawarode, Attaphol; Diaz, Miguel Angel; Prestidge, Tim; Rangarajan, Hemalatha G.; Ringden, Olle; Saad, Ayman; Savani, Bipin N.; Schoemans, Hélène; Seo, Sachiko; Schultz, Kirk R.; Solh, Melhem; Spitzer, Thomas; Storek, Jan; Teshima, Takanori; Verdonck, Leo F.; Wirk, Baldeep; Yared, Jean A.; Cahn, Jean-Yves; Weisdorf, Daniel J.; Medicine, School of MedicinePurpose: There is no consensus on the best choice of an alternative donor (umbilical cord blood [UCB], haploidentical, one-antigen mismatched [7/8]-bone marrow [BM], or 7/8-peripheral blood [PB]) for hematopoietic cell transplantation (HCT) for patients lacking an HLA-matched related or unrelated donor. Methods: We report composite end points of graft-versus-host disease (GVHD)-free relapse-free survival (GRFS) and chronic GVHD (cGVHD)-free relapse-free survival (CRFS) in 2,198 patients who underwent UCB (n = 838), haploidentical (n = 159), 7/8-BM (n = 241), or 7/8-PB (n = 960) HCT. All groups were divided by myeloablative conditioning (MAC) intensity or reduced intensity conditioning (RIC), except haploidentical group in which most received RIC. To account for multiple testing, P < .0071 in multivariable analysis and P < .00025 in direct pairwise comparisons were considered statistically significant. Results: In multivariable analysis, haploidentical group had the best GRFS, CRFS, and overall survival (OS). In the direct pairwise comparison of other groups, among those who received MAC, there was no difference in GRFS or CRFS among UCB, 7/8-BM, and 7/8-PB with serotherapy (alemtuzumab or antithymocyte globulin) groups. In contrast, the 7/8-PB without serotherapy group had significantly inferior GRFS, higher cGVHD, and a trend toward worse CRFS (hazard ratio [HR], 1.38; 95% CI, 1.13 to 1.69; P = .002) than the 7/8-BM group and higher cGVHD and trend toward inferior CRFS (HR, 1.36; 95% CI, 1.14 to 1.63; P = .0006) than the UCB group. Among patients with RIC, all groups had significantly inferior GRFS and CRFS compared with the haploidentical group. Conclusion: Recognizing the limitations of a registry retrospective analysis and the possibility of center selection bias in choosing donors, our data support the use of UCB, 7/8-BM, or 7/8-PB (with serotherapy) grafts for patients undergoing MAC HCT and haploidentical grafts for patients undergoing RIC HCT. The haploidentical group had the best GRFS, CRFS, and OS of all groups.Item A distinct X-linked syndrome involving joint contractures, keloids, large optic cup-to-disc ratio, and renal stones results from a filamin A (FLNA) mutation(Wiley, 2016-04-01) Lah, Melissa; Niranjan, Tejasvi; Srikanth, Sujata; Holloway, Lynda; Schwartz, Charles E.; Wang, Tao; Weaver, David D.; Medical and Molecular Genetics, School of MedicineWe further evaluated a previously reported family with an apparently undescribed X-linked syndrome involving joint contractures, keloids, an increased optic cup-to-disc ratio, and renal stones to elucidate the genetic cause. To do this, we obtained medical histories and performed physical examination on 14 individuals in the family, five of whom are affected males and three are obligate carrier females. Linkage analysis was performed on all but one individual and chromosome X-exome sequencing was done on two affected males. The analysis localized the putative gene to Xq27-qter and chromosome X-exome sequencing revealed a mutation in exon 28 (c.4726G>A) of the filamin A (FLNA) gene, predicting that a conserved glycine had been replaced by arginine at amino acid 1576 (p.G1576R). Segregation analysis demonstrated that all known carrier females tested were heterozygous (G/A), all affected males were hemizygous for the mutation (A allele) and all normal males were hemizygous for the normal G allele. The data and the bioinformatic analysis indicate that the G1576R mutation in the FLNA gene is very likely pathogenic in this family. The syndrome affecting the family shares phenotypic overlap with other syndromes caused by FLNA mutations, but appears to be a distinct phenotype, likely representing a unique genetic syndrome. © 2016 Wiley Periodicals, Inc.Item GPR68 Is a Neuroprotective Proton Receptor in Brain Ischemia(Lippincott, Williams & Wilkins, 2020-12) Wang, Tao; Zhou, Guokun; He, Mindi; Xu, Yuanyuan; Rusyniak, W.G.; Xu, Yan; Ji, Yonghua; Simon, Roger P.; Xiong, Zhi-Gang; Zha, Xiang-ming; Obstetrics and Gynecology, School of MedicineBrain acidosis is prevalent in stroke and other neurological diseases. Acidosis can have paradoxical injurious and protective effects. The purpose of this study is to determine whether a proton receptor exists in neurons to counteract acidosis-induced injury. Methods: We analyzed the expression of proton-sensitive GPCRs (G protein-coupled receptors) in the brain, examined acidosis-induced signaling in vitro, and studied neuronal injury using in vitro and in vivo mouse models. Results: GPR68, a proton-sensitive GPCR, was present in both mouse and human brain, and elicited neuroprotection in acidotic and ischemic conditions. GPR68 exhibited wide expression in brain neurons and mediated acidosis-induced PKC (protein kinase C) activation. PKC inhibition exacerbated pH 6-induced neuronal injury in a GPR68-dependent manner. Consistent with its neuroprotective function, GPR68 overexpression alleviated middle cerebral artery occlusion–induced brain injury. Conclusions: These data expand our knowledge on neuronal acid signaling to include a neuroprotective metabotropic dimension and offer GPR68 as a novel therapeutic target to alleviate neuronal injuries in ischemia and multiple other neurological diseases.Item Impact of T Cell Dose on Outcome of T Cell-Replete HLA-Matched Allogeneic Peripheral Blood Stem Cell Transplantation(Elsevier, 2019) Saad, Ayman; Lamb, Lawrence; Wang, Tao; Hemmer, Michael T.; Spellman, Stephen; Couriel, Daniel; Alousi, Amin; Pidala, Joseph; Abdel-Azim, Hisham; Agrawal, Vaibhav; Aljurf, Mahmoud; Beitinjaneh, Amer M.; Bhatt, Vijaya Raj; Buchbinder, David; Byrne, Michael; Cahn, Jean-Yves; Cairo, Mitchell; Castillo, Paul; Chhabra, Saurabh; Diaz, Miguel Angel; Farhan, Shatha; Floisand, Yngvar; Frangoul, Hadar A.; Gadalla, Shahinaz M.; Gajewski, James; Gale, Robert Peter; Gandhi, Manish; Gergis, Usama; Hamilton, Betty Ky; Hematti, Peiman; Hildebrandt, Gerhard C.; Kamble, Rammurti T.; Kanate, Abraham S.; Khandelwal, Pooja; Lazaryn, Aleksandr; MacMillan, Margaret; Marks, David I.; Martino, Rodrigo; Mehta, Parinda A.; Nishihori, Taiga; Olsson, Richard F.; Patel, Sagar S.; Qayed, Muna; Rangarajan, Hemalatha G.; Reshef, Ran; Ringden, Olle; Savani, Bipin N.; Schouten, Harry C.; Schultz, Kirk R.; Seo, Sachiko; Shaffer, Brian C.; Solh, Melhem; Teshima, Takanori; Urbano-Ispizua, Alvaro; Verdonck, Leo F.; Vij, Ravi; Waller, Edmund K.; William, Basem; Wirk, Baldeep; Yared, Jean A.; Yu, Lolie C.; Arora, Mukta; Hashmi, Shahrukh; Medicine, School of MedicineData on whether the T cell dose of allogeneic peripheral blood stem cell (PBSC) products influences transplantation outcomes are conflicting. Using the Center for International Blood and Marrow Transplant Research database, we identified 2736 adult patients who underwent first allogeneic PBSC transplantation for acute leukemia or myelodysplastic syndrome between 2008 and 2014 using an HLA-matched sibling donor (MSD) or an 8/8-matched unrelated donor (MUD). We excluded ex vivo and in vivo T cell-depleted transplantations. Correlative analysis was performed between CD3+ T cell dose and the risk of graft-versus-host-disease (GVHD), relapse, nonrelapse mortality (NRM), disease-free survival (DFS), and overall survival (OS). Using maximum likelihood estimation, we identified CD3+ T cell dose cutoff that separated the risk of acute GVHD (aGVHD) grade II-IV in both the MSD and MUD groups. A CD3+ T cell dose cutoff of 14 × 107 cells/kg identified MSD/low CD3+ (n = 223) and MSD/high CD3+ (n = 1214), and a dose of 15 × 107 cells/kg identified MUD/low CD3+ (n = 197) and MUD/high CD3+ (n = 1102). On univariate analysis, the MSD/high CD3+ group had a higher cumulative incidence of day +100 aGVHD grade II-IV compared with the MSD/low CD3+ group (33% versus 25%; P = .009). There were no differences between the 2 groups in engraftment rate, risk of aGVHD grade III-IV or chronic GVHD (cGVHD), NRM, relapse, DFS, or OS. The MUD/high CD3+ group had a higher cumulative incidence of day +100 aGVHD grade II-IV compared with the MUD/low CD3+ group (49% versus 41%; P = .04). There were no differences between the 2 groups in engraftment rate, risk of severe aGVHD or cGVHD, NRM, relapse, DFS, or OS. Multivariate analysis of the MSD and MUD groups failed to show an association between CD3+ T cell dose and the risk of either aGVHD grade II-IV (P = .10 and .07, respectively) or cGVHD (P = .80 and .30, respectively). Subanalysis of CD4+ T cells, CD8+ T cells, and CD4+/CD8+ ratio failed to identify cutoff values predictive of transplantation outcomes; however, using the log-rank test, the sample size was suboptimal for identifying a difference at this cutoff cell dose. In this registry study, the CD3+ T cell dose of PBSC products did not influence the risk of aGVHD or cGVHD or other transplantation outcomes when using an MSD or an 8/8-matched MUD. Subset analyses of CD4+ and CD8+ T cell doses were not possible given our small sample size.Item In Vivo Identification and Manipulation of the Ca2+ Selectivity Filter in the Drosophila Transient Receptor Potential Channel(Society for Neuroscience, 2007-01-17) Liu, Che H.; Wang, Tao; Postma, Marten; Obukhov, Alexander G.; Montell, Craig; Hardie, Roger C.; Cellular and Integrative Physiology, School of MedicineNull mutations in the transient receptor potential (trp) gene eliminate the major, Ca2+-selective component of the light-sensitive conductance in Drosophila photoreceptors. Although it is the prototypical member of the TRP ion channel superfamily, conclusive evidence that TRP is a pore-forming channel subunit in vivo is lacking. We show here that mutating a specific acidic residue (Asp621) in the putative pore virtually eliminated Ca2+ permeation in vivo and altered other biophysical properties of the native TRP conductance. The results identify Asp621 as a critical residue of the TRP Ca2+ selectivity filter, provide the first rigorous demonstration that a TRP protein is a pore-forming subunit in any native system, and point to the likely location of the pore in mammalian canonical TRP channels. The specific elimination of Ca2+ permeation in TRP also provided a unique opportunity to address the roles of Ca2+ influx in vivo. We found that Asp621 mutations profoundly affected several key aspects of the light response and caused light-dependent retinal degeneration.Item Multi-omic profiling of clear cell renal cell carcinoma identifies metabolic reprogramming associated with disease progression(Springer Nature, 2024) Hu, Junyi; Wang, Shao-Gang; Hou, Yaxin; Chen, Zhaohui; Liu, Lilong; Li, Ruizhi; Li, Nisha; Zhou, Lijie; Yang, Yu; Wang, Liping; Wang, Liang; Yang, Xiong; Lei, Yichen; Deng, Changqi; Li, Yang; Deng, Zhiyao; Ding, Yuhong; Kuang, Yingchun; Yao, Zhipeng; Xun, Yang; Li, Fan; Li, Heng; Hu, Jia; Liu, Zheng; Wang, Tao; Hao, Yi; Jiao, Xuanmao; Guan, Wei; Tao, Zhen; Ren, Shancheng; Chen, Ke; Pathology and Laboratory Medicine, School of MedicineClear cell renal cell carcinoma (ccRCC) is a complex disease with remarkable immune and metabolic heterogeneity. Here we perform genomic, transcriptomic, proteomic, metabolomic and spatial transcriptomic and metabolomic analyses on 100 patients with ccRCC from the Tongji Hospital RCC (TJ-RCC) cohort. Our analysis identifies four ccRCC subtypes including De-clear cell differentiated (DCCD)-ccRCC, a subtype with distinctive metabolic features. DCCD cancer cells are characterized by fewer lipid droplets, reduced metabolic activity, enhanced nutrient uptake capability and a high proliferation rate, leading to poor prognosis. Using single-cell and spatial trajectory analysis, we demonstrate that DCCD is a common mode of ccRCC progression. Even among stage I patients, DCCD is associated with worse outcomes and higher recurrence rate, suggesting that it cannot be cured by nephrectomy alone. Our study also suggests a treatment strategy based on subtype-specific immune cell infiltration that could guide the clinical management of ccRCC.Item Multiple functional variants in the IL1RL1 region are pretransplant markers for risk of GVHD and infection deaths(American Society of Hematology, 2019-08-27) Karaesmen, Ezgi; Hahn, Theresa; Dile, Alexander James; Rizvi, Abbas A.; Wang, Junke; Wang, Tao; Haagenson, Michael D.; Preus, Leah; Zhu, Qianqian; Liu, Qian; Yan, Li; Liu, Song; Haiman, Christopher A.; Stram, Daniel; Pooler, Loreall; Sheng, Xin; Van Den Berg, David; Brock, Guy; Webb, Amy; McCarthy, Philip L.; Pasquini, Marcelo C.; Spellman, Stephen R.; Lee, Stephanie J.; Paczesny, Sophie; Sucheston-Campbell, Lara E.; Pediatrics, School of MedicineGraft-versus-host disease (GVHD) and infections are the 2 main causes of death without relapse after allogeneic hematopoietic cell transplantation (HCT). Elevated soluble serum simulation-2 (sST2), the product of IL1RL1 in plasma/serum post-HCT, is a validated GVHD biomarker. Hundreds of SNPs at 2q12.1 have been shown to be strongly associated with sST2 concentrations in healthy populations. We therefore hypothesized that the donor genetic variants in IL1RL1 correlate with sST2 protein levels associated with patient survival outcomes after HCT. We used DISCOVeRY-BMT (Determining the Influence of Susceptibility Conveying Variants Related to 1-Year Mortality after Blood and Marrow Transplantation), a genomic study of >3000 donor-recipient pairs, to inform our hypothesis. We first measured pre-HCT plasma/serum sST2 levels in a subset of DISCOVeRY-BMT donors (n = 757) and tested the association of donor sST2 levels with donor single nucleotide polymorphisms (SNPs) in the 2q12.1 region. Donor SNPs associated with sST2 levels were then tested for association with recipient death caused by acute GVHD (aGVHD)-, infection-, and transplant-related mortality in cohorts 1 and 2. Meta-analyses of cohorts 1 and 2 were performed using fixed-effects inverse variance weighting, and P values were corrected for multiple comparisons. Donor risk alleles in rs22441131 (P meta = .00026) and rs2310241 (P meta = .00033) increased the cumulative incidence of aGVHD death up to fourfold and were associated with high sST2 levels. Donor risk alleles at rs4851601 (P meta = 9.7 × 10-7), rs13019803 (P meta = 8.9 × 10-6), and rs13015714 (P meta = 5.3 × 10-4) increased cumulative incidence of infection death to almost sevenfold and were associated with low sST2 levels. These functional variants are biomarkers of infection or aGVHD death and could facilitate donor selection, prophylaxis, and a conditioning regimen to reduce post-HCT mortality.