Hongwei Yin - Academia.edu (original) (raw)

Papers by Hongwei Yin

European Journal of Cancer Supplements, 2006

Oncotarget, Jan 11, 2016

Therapies targeting the tyrosine kinase activity of Epidermal Growth Factor Receptor (EGFR) have ... more Therapies targeting the tyrosine kinase activity of Epidermal Growth Factor Receptor (EGFR) have been proven to be effective in treating a subset of non-small cell lung cancer (NSCLC) patients harboring activating EGFR mutations. Inevitably these patients develop resistance to the EGFR-targeted tyrosine kinase inhibitors (TKIs). Here, we performed integrated genomic analyses using an in vitro system to uncover alternative genomic mechanisms responsible for acquired resistance to EGFR-TKIs. Specifically, we identified 80 genes whose expression is significantly increased in the erlotinib-resistant clones. RNAi-based systematic synthetic lethal screening of these candidate genes revealed that suppression of one upregulated transcript, SCRN1, a secernin family member, restores sensitivity to erlotinib by enhancing inhibition of PI3K/AKT signaling pathway. Furthermore, immunohistochemical analysis revealed increased levels of SCRN1 in 5 of 11 lung tumor specimens from EGFR-TKIs resistant...

Mathematische Nachrichten, Dec 1, 2014

Let be a strictly stationary sequence of negatively associated random variables with zero mean an... more Let be a strictly stationary sequence of negatively associated random variables with zero mean and finite variance. We set and , . If , then for any , we show the precise rates of the first moment convergence in the law of the iterated logarithm for a kind of weighted infinite series of and as , and as .

Cancer research, Jan 24, 2015

Disrupting the eukaryotic translation initiation factor 4F (eIF4F) complex offers an appealing st... more Disrupting the eukaryotic translation initiation factor 4F (eIF4F) complex offers an appealing strategy to potentiate the effectiveness of existing cancer therapies and to overcome resistance to drugs such as BRAF inhibitors (BRAFi). Here, we identified and characterized the small molecule SBI-0640756 (SBI-756), a first-in-class inhibitor that targets eIF4G1 and disrupts the eIF4F complex. SBI-756 impaired the eIF4F complex assembly independently of mTOR and attenuated growth of BRAF-resistant and BRAF-independent melanomas. SBI-756 also suppressed AKT and NF-κB signaling, but small-molecule derivatives were identified that only marginally affected these pathways while still inhibiting eIF4F complex formation and melanoma growth, illustrating the potential for further structural and functional manipulation of SBI-756 as a drug lead. In the gene expression signature patterns elicited by SBI-756, DNA damage, and cell-cycle regulatory factors were prominent, with mutations in melanoma ...

International Journal of Biomathematics, 2014

ABSTRACT In biological development, morphogens are locally produced and spread to other regions i... more ABSTRACT In biological development, morphogens are locally produced and spread to other regions in organs, forming gradients that control the inter-related pattern and growth of developing organs. Mechanisms of morphogen transport were built and investigated by numerical simulations in [A. D. Lander, Q. Nie and F. Y. M. Wan, Do morphogen gradients arise by diffusion? Developmental Cell2 (2002) 785-796]. In that paper, model C, which considers endocytosis, exocytosis and receptor synthesis and degradation, is in a one-dimensional spatial region and couples a partial differential equation with ordinary differential equations. Here, this model is promoted to an arbitrary dimension bounded region. We prove existence, uniqueness and non-negativity of a global solution for this advanced model, of its steady-state solution and linear stability of steady state by operator semigroup, the Schauder theorem and local perturbation method. Our results improve previous results for this model in a one dimension region.

Chaos, Solitons & Fractals, 2014

ABSTRACT In this paper, a diffusive Leslie–Gower predator–prey system with nonmonotonic functiona... more ABSTRACT In this paper, a diffusive Leslie–Gower predator–prey system with nonmonotonic functional respond is studied. We obtain the persistence of this model and show the local asymptotic stability of positive constant equilibrium by linearized analysis and the global stability by constructing Liapunov function. Besides, Turing instability of this equilibrium is obtained. The existence and nonexistence of positive nonconstant steady states of this model are established. Furthermore, by numerical simulations we illustrate the patterns of prey and predator.

International Journal of Biomathematics

In biological development, morphogens are locally produced and spread to other regions in organs,... more In biological development, morphogens are locally produced and spread to other regions in organs, forming gradients that control the inter-related pattern and growth of developing organs. Mechanisms of morphogen transport were built and investigated by numerical simulations in [A. D. Lander, Q. Nie and F. Y. M. Wan, Do morphogen gradients arise by diffusion? Developmental Cell2 (2002) 785-796]. In that paper, model C, which considers endocytosis, exocytosis and receptor synthesis and degradation, is in a one-dimensional spatial region and couples a partial differential equation with ordinary differential equations. Here, this model is promoted to an arbitrary dimension bounded region. We prove existence, uniqueness and non-negativity of a global solution for this advanced model, of its steady-state solution and linear stability of steady state by operator semigroup, the Schauder theorem and local perturbation method. Our results improve previous results for this model in a one dimen...

Tectonophysics, 2014

The co-seismic slip sense of the 2008 Wenchuan earthquake (Mw 7.9) has resulted in the present ea... more The co-seismic slip sense of the 2008 Wenchuan earthquake (Mw 7.9) has resulted in the present east-west (E-W) crustal shortening and oblique thrusting across Longmen Shan, which are inconsistent with southeast-directed thrusting that occurred during the late Triassic. Although the two major periods of compressional deformations in Longmen Shan have long been recognized, the fault slip rate of the late Cenozoic deformation and the initial E-W crustal shortening remain poorly investigated. This study confirms the fault slip rate in the Dayi Thrust Fault System (DYFS) based on data from the petroleum industry and shallow seismic reflection profiles, and well data. Folded late Pliocene to present strata are analyzed and yield with an average slip rate of 0.2 mm/yr on the DYFS. An average fault slip rate of 0.25 mm/yr is then obtained from the late Pliocene to present for the range front thrust of Longmen Shan. The E-W crustal shortening is investigated by using 3-D seismic reflection data, interpreting satellite image, and conducting a field investigation in the DYFS to determine stress field changes during the late Cenozoic. Two-period tectonic deformations during the late Cenozoic are found in the DYFS, which correspond to the NE-and NS-trending structures, respectively. The activities of the DYFS may reflect a change in the field direction of the regional stress-from NW-SE during the Oligocene to early Pliocene to E-W during the late Pliocene to Holocene, which is consistent with the present stress measurements. The 120 km NS-trending structures in the southern Longmen Shan range front as well as the Wenchuan earthquake co-seismic ruptures are assumed to reflect the active, E-W crustal shortening in Longmen Shan.

Molecular Cancer Research, 2014

Acta Geologica Sinica - English Edition, 2014

Nature, Jan 31, 2000

Coordination of spindle orientation with the axis of cell division is an essential process in all... more Coordination of spindle orientation with the axis of cell division is an essential process in all eukaryotes. In addition to ensuring accurate chromosomal segregation, proper spindle orientation also establishes differential cell fates and proper morphogenesis. In both animal and yeast cells, this process is dependent on cytoplasmic microtubules interacting with the cortical actin-based cytoskeleton, although the motive force was unknown. Here we show that yeast Myo2, a myosin V that translocates along polarized actin cables into the bud, orientates the spindle early in the cell cycle by binding and polarizing the microtubule-associated protein Kar9 (refs 7-9). The tail domain of Myo2 that binds Kar9 also interacts with secretory vesicles and vacuolar elements, making it a pivotal component of yeast cell polarization.

Blood, Jan 15, 2015

To identify molecular targets that modify sensitivity to lenalidomide, we measured proliferation ... more To identify molecular targets that modify sensitivity to lenalidomide, we measured proliferation in multiple myeloma (MM) cells transfected with 27 968 small interfering RNAs in the presence of increasing concentrations of drug and identified 63 genes that enhance activity of lenalidomide upon silencing. Ribosomal protein S6 kinase (RPS6KA3 or RSK2) was the most potent sensitizer. Other notable gene targets included 5 RAB family members, 3 potassium channel proteins, and 2 peroxisome family members. Single genes of interest included I-κ-B kinase-α (CHUK), and a phosphorylation dependent transcription factor (CREB1), which associate with RSK2 to regulate several signaling pathways. RSK2 knockdown induced cytotoxicity across a panel of MM cell lines and consistently increased sensitivity to lenalidomide. Accordingly, 3 small molecular inhibitors of RSK2 demonstrated synergy with lenalidomide cytotoxicity in MM cells even in the presence of stromal contact. Both RSK2 knockdown and smal...

Marine and Petroleum Geology, 2015

(1): salt structures in the Precaspian Basin are analyzed using scaled sandbox model.

Cancer research, Jan 24, 2015

Melanoma development involves members of the AGC kinase family including AKT, PKC and, most recen... more Melanoma development involves members of the AGC kinase family including AKT, PKC and, most recently, PDK1, as elucidated recently in studies of Braf::Pten mutant melanomas. Here we report that PDK1 contributes functionally to skin pigmentation and to the development of melanomas harboring a wild-type PTEN genotype, which occurs in ~70% of human melanomas. The PDK1 substrate SGK3 was determined to be is an important mediator of PDK1 activities in melanoma cells. Genetic or pharmacological inhibition of PDK1 and SGK3 attenuated melanoma growth by inducing G1 phase cell cycle arrest. In a synthetic lethal screen, pan-PI3K inhibition synergized with PDK1 inhibition to suppress melanoma growth, suggesting that focused blockade of PDK1/PI3K signaling might offer a new therapeutic modality for wild-type PTEN tumors. We also noted that responsiveness to PDK1 inhibition associated with decreased expression of pigmentation genes and increased expression of cytokines and inflammatory genes, s...

Nature Genetics

1 6 5 l e t t e r s We sequenced eight melanoma exomes to identify new somatic mutations in metas... more 1 6 5 l e t t e r s We sequenced eight melanoma exomes to identify new somatic mutations in metastatic melanoma. Focusing on the mitogen-activated protein (MAP) kinase kinase kinase (MAP3K) family, we found that 24% of melanoma cell lines have mutations in the protein-coding regions of either MAP3K5 or MAP3K9. Structural modeling predicted that mutations in the kinase domain may affect the activity and regulation of these protein kinases. The position of the mutations and the loss of heterozygosity of MAP3K5 and MAP3K9 in 85% and 67% of melanoma samples, respectively, together suggest that the mutations are likely to be inactivating. In in vitro kinase assays, MAP3K5 I780F and MAP3K9 W333* variants had reduced kinase activity. Overexpression of MAP3K5 or MAP3K9 mutants in HEK293T cells reduced the phosphorylation of downstream MAP kinases. Attenuation of MAP3K9 function in melanoma cells using siRNA led to increased cell viability after temozolomide treatment, suggesting that decreased MAP3K pathway activity can lead to chemoresistance in melanoma.

Methods in Molecular Biology, 2009

High-throughput RNA interference (HT-RNAi) is a powerful research tool for parallel, &amp... more High-throughput RNA interference (HT-RNAi) is a powerful research tool for parallel, 'genome-wide', targeted knockdown of specific gene products. Such perturbation of gene product expression allows for the systematic query of gene function. The phenotypic results can be monitored by assaying for specific alterations in molecular and cellular endpoints, such as promoter activation, cell proliferation and survival. RNAi profiling may also be coupled with drug screening to identify molecular correlates of drug response. As with other genomic-scale data, methods of data analysis are required to handle the unique aspects of data normalization and statistical processing. In addition, novel techniques or knowledge-mining strategies are required to extract useful biological information from HT-RNAi data. Knowledge-mining strategies involve the novel application of bioinformatic tools and expert curation to provide biological context to genomic-scale data such as that generated from HT-RNAi data. Pathway-based tools, whether text-mining based or manually curated, serve an essential role in knowledge mining. These tools can be applied during all steps of HT-RNAi screen experiments including pre-screen knowledge gathering, assay development and hit confirmation and validation. Most importantly, pathway tools allow the interrogation of HT-RNAi data to identify and prioritize pathway-based biological information as a result of specific loss of gene function.

European Journal of Cancer Supplements, 2006

Oncotarget, Jan 11, 2016

Therapies targeting the tyrosine kinase activity of Epidermal Growth Factor Receptor (EGFR) have ... more Therapies targeting the tyrosine kinase activity of Epidermal Growth Factor Receptor (EGFR) have been proven to be effective in treating a subset of non-small cell lung cancer (NSCLC) patients harboring activating EGFR mutations. Inevitably these patients develop resistance to the EGFR-targeted tyrosine kinase inhibitors (TKIs). Here, we performed integrated genomic analyses using an in vitro system to uncover alternative genomic mechanisms responsible for acquired resistance to EGFR-TKIs. Specifically, we identified 80 genes whose expression is significantly increased in the erlotinib-resistant clones. RNAi-based systematic synthetic lethal screening of these candidate genes revealed that suppression of one upregulated transcript, SCRN1, a secernin family member, restores sensitivity to erlotinib by enhancing inhibition of PI3K/AKT signaling pathway. Furthermore, immunohistochemical analysis revealed increased levels of SCRN1 in 5 of 11 lung tumor specimens from EGFR-TKIs resistant...

Mathematische Nachrichten, Dec 1, 2014

Let be a strictly stationary sequence of negatively associated random variables with zero mean an... more Let be a strictly stationary sequence of negatively associated random variables with zero mean and finite variance. We set and , . If , then for any , we show the precise rates of the first moment convergence in the law of the iterated logarithm for a kind of weighted infinite series of and as , and as .

Cancer research, Jan 24, 2015

Disrupting the eukaryotic translation initiation factor 4F (eIF4F) complex offers an appealing st... more Disrupting the eukaryotic translation initiation factor 4F (eIF4F) complex offers an appealing strategy to potentiate the effectiveness of existing cancer therapies and to overcome resistance to drugs such as BRAF inhibitors (BRAFi). Here, we identified and characterized the small molecule SBI-0640756 (SBI-756), a first-in-class inhibitor that targets eIF4G1 and disrupts the eIF4F complex. SBI-756 impaired the eIF4F complex assembly independently of mTOR and attenuated growth of BRAF-resistant and BRAF-independent melanomas. SBI-756 also suppressed AKT and NF-κB signaling, but small-molecule derivatives were identified that only marginally affected these pathways while still inhibiting eIF4F complex formation and melanoma growth, illustrating the potential for further structural and functional manipulation of SBI-756 as a drug lead. In the gene expression signature patterns elicited by SBI-756, DNA damage, and cell-cycle regulatory factors were prominent, with mutations in melanoma ...

International Journal of Biomathematics, 2014

ABSTRACT In biological development, morphogens are locally produced and spread to other regions i... more ABSTRACT In biological development, morphogens are locally produced and spread to other regions in organs, forming gradients that control the inter-related pattern and growth of developing organs. Mechanisms of morphogen transport were built and investigated by numerical simulations in [A. D. Lander, Q. Nie and F. Y. M. Wan, Do morphogen gradients arise by diffusion? Developmental Cell2 (2002) 785-796]. In that paper, model C, which considers endocytosis, exocytosis and receptor synthesis and degradation, is in a one-dimensional spatial region and couples a partial differential equation with ordinary differential equations. Here, this model is promoted to an arbitrary dimension bounded region. We prove existence, uniqueness and non-negativity of a global solution for this advanced model, of its steady-state solution and linear stability of steady state by operator semigroup, the Schauder theorem and local perturbation method. Our results improve previous results for this model in a one dimension region.

Chaos, Solitons & Fractals, 2014

ABSTRACT In this paper, a diffusive Leslie–Gower predator–prey system with nonmonotonic functiona... more ABSTRACT In this paper, a diffusive Leslie–Gower predator–prey system with nonmonotonic functional respond is studied. We obtain the persistence of this model and show the local asymptotic stability of positive constant equilibrium by linearized analysis and the global stability by constructing Liapunov function. Besides, Turing instability of this equilibrium is obtained. The existence and nonexistence of positive nonconstant steady states of this model are established. Furthermore, by numerical simulations we illustrate the patterns of prey and predator.

International Journal of Biomathematics

In biological development, morphogens are locally produced and spread to other regions in organs,... more In biological development, morphogens are locally produced and spread to other regions in organs, forming gradients that control the inter-related pattern and growth of developing organs. Mechanisms of morphogen transport were built and investigated by numerical simulations in [A. D. Lander, Q. Nie and F. Y. M. Wan, Do morphogen gradients arise by diffusion? Developmental Cell2 (2002) 785-796]. In that paper, model C, which considers endocytosis, exocytosis and receptor synthesis and degradation, is in a one-dimensional spatial region and couples a partial differential equation with ordinary differential equations. Here, this model is promoted to an arbitrary dimension bounded region. We prove existence, uniqueness and non-negativity of a global solution for this advanced model, of its steady-state solution and linear stability of steady state by operator semigroup, the Schauder theorem and local perturbation method. Our results improve previous results for this model in a one dimen...

Tectonophysics, 2014

The co-seismic slip sense of the 2008 Wenchuan earthquake (Mw 7.9) has resulted in the present ea... more The co-seismic slip sense of the 2008 Wenchuan earthquake (Mw 7.9) has resulted in the present east-west (E-W) crustal shortening and oblique thrusting across Longmen Shan, which are inconsistent with southeast-directed thrusting that occurred during the late Triassic. Although the two major periods of compressional deformations in Longmen Shan have long been recognized, the fault slip rate of the late Cenozoic deformation and the initial E-W crustal shortening remain poorly investigated. This study confirms the fault slip rate in the Dayi Thrust Fault System (DYFS) based on data from the petroleum industry and shallow seismic reflection profiles, and well data. Folded late Pliocene to present strata are analyzed and yield with an average slip rate of 0.2 mm/yr on the DYFS. An average fault slip rate of 0.25 mm/yr is then obtained from the late Pliocene to present for the range front thrust of Longmen Shan. The E-W crustal shortening is investigated by using 3-D seismic reflection data, interpreting satellite image, and conducting a field investigation in the DYFS to determine stress field changes during the late Cenozoic. Two-period tectonic deformations during the late Cenozoic are found in the DYFS, which correspond to the NE-and NS-trending structures, respectively. The activities of the DYFS may reflect a change in the field direction of the regional stress-from NW-SE during the Oligocene to early Pliocene to E-W during the late Pliocene to Holocene, which is consistent with the present stress measurements. The 120 km NS-trending structures in the southern Longmen Shan range front as well as the Wenchuan earthquake co-seismic ruptures are assumed to reflect the active, E-W crustal shortening in Longmen Shan.

Molecular Cancer Research, 2014

Acta Geologica Sinica - English Edition, 2014

Nature, Jan 31, 2000

Coordination of spindle orientation with the axis of cell division is an essential process in all... more Coordination of spindle orientation with the axis of cell division is an essential process in all eukaryotes. In addition to ensuring accurate chromosomal segregation, proper spindle orientation also establishes differential cell fates and proper morphogenesis. In both animal and yeast cells, this process is dependent on cytoplasmic microtubules interacting with the cortical actin-based cytoskeleton, although the motive force was unknown. Here we show that yeast Myo2, a myosin V that translocates along polarized actin cables into the bud, orientates the spindle early in the cell cycle by binding and polarizing the microtubule-associated protein Kar9 (refs 7-9). The tail domain of Myo2 that binds Kar9 also interacts with secretory vesicles and vacuolar elements, making it a pivotal component of yeast cell polarization.

Blood, Jan 15, 2015

To identify molecular targets that modify sensitivity to lenalidomide, we measured proliferation ... more To identify molecular targets that modify sensitivity to lenalidomide, we measured proliferation in multiple myeloma (MM) cells transfected with 27 968 small interfering RNAs in the presence of increasing concentrations of drug and identified 63 genes that enhance activity of lenalidomide upon silencing. Ribosomal protein S6 kinase (RPS6KA3 or RSK2) was the most potent sensitizer. Other notable gene targets included 5 RAB family members, 3 potassium channel proteins, and 2 peroxisome family members. Single genes of interest included I-κ-B kinase-α (CHUK), and a phosphorylation dependent transcription factor (CREB1), which associate with RSK2 to regulate several signaling pathways. RSK2 knockdown induced cytotoxicity across a panel of MM cell lines and consistently increased sensitivity to lenalidomide. Accordingly, 3 small molecular inhibitors of RSK2 demonstrated synergy with lenalidomide cytotoxicity in MM cells even in the presence of stromal contact. Both RSK2 knockdown and smal...

Marine and Petroleum Geology, 2015

(1): salt structures in the Precaspian Basin are analyzed using scaled sandbox model.

Cancer research, Jan 24, 2015

Melanoma development involves members of the AGC kinase family including AKT, PKC and, most recen... more Melanoma development involves members of the AGC kinase family including AKT, PKC and, most recently, PDK1, as elucidated recently in studies of Braf::Pten mutant melanomas. Here we report that PDK1 contributes functionally to skin pigmentation and to the development of melanomas harboring a wild-type PTEN genotype, which occurs in ~70% of human melanomas. The PDK1 substrate SGK3 was determined to be is an important mediator of PDK1 activities in melanoma cells. Genetic or pharmacological inhibition of PDK1 and SGK3 attenuated melanoma growth by inducing G1 phase cell cycle arrest. In a synthetic lethal screen, pan-PI3K inhibition synergized with PDK1 inhibition to suppress melanoma growth, suggesting that focused blockade of PDK1/PI3K signaling might offer a new therapeutic modality for wild-type PTEN tumors. We also noted that responsiveness to PDK1 inhibition associated with decreased expression of pigmentation genes and increased expression of cytokines and inflammatory genes, s...

Nature Genetics

1 6 5 l e t t e r s We sequenced eight melanoma exomes to identify new somatic mutations in metas... more 1 6 5 l e t t e r s We sequenced eight melanoma exomes to identify new somatic mutations in metastatic melanoma. Focusing on the mitogen-activated protein (MAP) kinase kinase kinase (MAP3K) family, we found that 24% of melanoma cell lines have mutations in the protein-coding regions of either MAP3K5 or MAP3K9. Structural modeling predicted that mutations in the kinase domain may affect the activity and regulation of these protein kinases. The position of the mutations and the loss of heterozygosity of MAP3K5 and MAP3K9 in 85% and 67% of melanoma samples, respectively, together suggest that the mutations are likely to be inactivating. In in vitro kinase assays, MAP3K5 I780F and MAP3K9 W333* variants had reduced kinase activity. Overexpression of MAP3K5 or MAP3K9 mutants in HEK293T cells reduced the phosphorylation of downstream MAP kinases. Attenuation of MAP3K9 function in melanoma cells using siRNA led to increased cell viability after temozolomide treatment, suggesting that decreased MAP3K pathway activity can lead to chemoresistance in melanoma.

Methods in Molecular Biology, 2009

High-throughput RNA interference (HT-RNAi) is a powerful research tool for parallel, &amp... more High-throughput RNA interference (HT-RNAi) is a powerful research tool for parallel, 'genome-wide', targeted knockdown of specific gene products. Such perturbation of gene product expression allows for the systematic query of gene function. The phenotypic results can be monitored by assaying for specific alterations in molecular and cellular endpoints, such as promoter activation, cell proliferation and survival. RNAi profiling may also be coupled with drug screening to identify molecular correlates of drug response. As with other genomic-scale data, methods of data analysis are required to handle the unique aspects of data normalization and statistical processing. In addition, novel techniques or knowledge-mining strategies are required to extract useful biological information from HT-RNAi data. Knowledge-mining strategies involve the novel application of bioinformatic tools and expert curation to provide biological context to genomic-scale data such as that generated from HT-RNAi data. Pathway-based tools, whether text-mining based or manually curated, serve an essential role in knowledge mining. These tools can be applied during all steps of HT-RNAi screen experiments including pre-screen knowledge gathering, assay development and hit confirmation and validation. Most importantly, pathway tools allow the interrogation of HT-RNAi data to identify and prioritize pathway-based biological information as a result of specific loss of gene function.