Colorectal cancer ranks third among the estimatedcancer cases and cancer related mortalities in United States in 2014. Early detection and efficient therapy remains a significant clinical challenge for this disease. T...Colorectal cancer ranks third among the estimatedcancer cases and cancer related mortalities in United States in 2014. Early detection and efficient therapy remains a significant clinical challenge for this disease. Therefore, there is a need to identify novel tumor asso-ciated molecules to target for biomarker development and immunotherapy. In this regard, cancer testis antigens have emerged as a potential targets for developing novel clinical biomarkers and immunotherapy for various malignancies. These germ cell specific proteins exhibit aberrant expression in cancer cells and contribute in tumorigenesis. Owing to their unique expression profile and immunogenicity in cancer patients, cancer testis antigens are clinically referred as the most promising tumor associated antigens. Several cancer testis antigens have been studied in colorectal cancer but none of them could be used in clinical practice. This review is an attempt to address the promising cancer testis antigens in colorectal cancer and their possible clinical implications as biomarkers and immunotherapeutic targets with particular focus on challenges and future interventions.展开更多
Regulatory T cells(Tregs)play a pivotal role in immune-tolerance,and loss of Treg function can lead to the development of autoimmunity.Natural Tregs generated in the thymus substantially contribute to the Treg pool in...Regulatory T cells(Tregs)play a pivotal role in immune-tolerance,and loss of Treg function can lead to the development of autoimmunity.Natural Tregs generated in the thymus substantially contribute to the Treg pool in the periphery,where they suppress self-reactive effector T cells(Teff)responses.Recently,we showed that OX40L(TNFSF4)is able to drive selective proliferation of peripheral Tregs independent of canonical antigen presentation(CAP-independent)in the presence of low-dose IL-2.Therefore,we hypothesized that OX40 signaling might be integral to the TCR-independent phase of murine and human thymic Treg(tTreg)development.Development of tTregs is a two-step process:Strong T-cell receptor(TCR)signals in combination with co-signals from the TNFRSF members facilitate tTreg precursor selection,followed by a TCR-independent phase of tTreg development in which their maturation is driven by IL-2.Therefore,we investigated whether OX40 signaling could also play a critical role in the TCR-independent phase of tTreg development.OX40−/−mice had significantly reduced numbers of CD25−Foxp3low tTreg precursors and CD25+Foxp3+mature tTregs,while OX40L treatment of WT mice induced significant proliferation of these cell subsets.Relative to tTeff cells,OX40 was expressed at higher levels in both murine and human tTreg precursors and mature tTregs.In ex vivo cultures,OX40L increased tTreg maturation and induced CAP-independent proliferation of both murine and human tTregs,which was mediated through the activation of AKT-mTOR signaling.These novel findings show an evolutionarily conserved role for OX40 signaling in tTreg development and proliferation,and might enable the development of novel strategies to increase Tregs and suppress autoimmunity.展开更多
The chemisorption energy is an integral aspect of surface chemistry,central to numerous fields such as catalysis,corrosion,and nanotechnology.Electronic-structure-based methods such as the Newns-Anderson model are the...The chemisorption energy is an integral aspect of surface chemistry,central to numerous fields such as catalysis,corrosion,and nanotechnology.Electronic-structure-based methods such as the Newns-Anderson model are therefore of great importance in guiding the engineering of material surfaces with optimal properties.However,existing methods are inadequate for interpreting complex,multi-metallic systems.Herein,we introduce a physics-based chemisorption model for alloyed transition metal surfaces employing primarily metal d-band properties that accounts for perturbations in both the substrate and adsorbate electronic states upon interaction.Importantly,we show that adsorbate-induced changes in the adsorption site interact with its chemical environment leading to a second-order response in chemisorption energy with the d-filling of the neighboring atoms.We demonstrate the robustness of the model on a wide range of transition metal alloys with O,N,CH,and Li adsorbates yielding a mean absolute error of 0.13 eV versus density functional theory reference chemisorption energies.展开更多
基金Indo-UK Cancer Research ProgramNo.BT/IN/UK/NII/2006+3 种基金Centre for Molecular MedicineNo.BT/PR/14549/MED/14/1291NII-core funding,Department of BiotechnologyGovernment of India
文摘Colorectal cancer ranks third among the estimatedcancer cases and cancer related mortalities in United States in 2014. Early detection and efficient therapy remains a significant clinical challenge for this disease. Therefore, there is a need to identify novel tumor asso-ciated molecules to target for biomarker development and immunotherapy. In this regard, cancer testis antigens have emerged as a potential targets for developing novel clinical biomarkers and immunotherapy for various malignancies. These germ cell specific proteins exhibit aberrant expression in cancer cells and contribute in tumorigenesis. Owing to their unique expression profile and immunogenicity in cancer patients, cancer testis antigens are clinically referred as the most promising tumor associated antigens. Several cancer testis antigens have been studied in colorectal cancer but none of them could be used in clinical practice. This review is an attempt to address the promising cancer testis antigens in colorectal cancer and their possible clinical implications as biomarkers and immunotherapeutic targets with particular focus on challenges and future interventions.
基金We thank the National Institutes of Health for grants #R01 AI107516-01Al and #1R41AI125039-01We thank the Juvenile Diabetes Research Foundation(JDRF)for grant #2-SRA-2016-245-S-B to Dr.PrabhakarWe thank the American Heart Association for offering apost-doctoral fellowship #15POST25090228 to PK.
文摘Regulatory T cells(Tregs)play a pivotal role in immune-tolerance,and loss of Treg function can lead to the development of autoimmunity.Natural Tregs generated in the thymus substantially contribute to the Treg pool in the periphery,where they suppress self-reactive effector T cells(Teff)responses.Recently,we showed that OX40L(TNFSF4)is able to drive selective proliferation of peripheral Tregs independent of canonical antigen presentation(CAP-independent)in the presence of low-dose IL-2.Therefore,we hypothesized that OX40 signaling might be integral to the TCR-independent phase of murine and human thymic Treg(tTreg)development.Development of tTregs is a two-step process:Strong T-cell receptor(TCR)signals in combination with co-signals from the TNFRSF members facilitate tTreg precursor selection,followed by a TCR-independent phase of tTreg development in which their maturation is driven by IL-2.Therefore,we investigated whether OX40 signaling could also play a critical role in the TCR-independent phase of tTreg development.OX40−/−mice had significantly reduced numbers of CD25−Foxp3low tTreg precursors and CD25+Foxp3+mature tTregs,while OX40L treatment of WT mice induced significant proliferation of these cell subsets.Relative to tTeff cells,OX40 was expressed at higher levels in both murine and human tTreg precursors and mature tTregs.In ex vivo cultures,OX40L increased tTreg maturation and induced CAP-independent proliferation of both murine and human tTregs,which was mediated through the activation of AKT-mTOR signaling.These novel findings show an evolutionarily conserved role for OX40 signaling in tTreg development and proliferation,and might enable the development of novel strategies to increase Tregs and suppress autoimmunity.
基金J.H.S.gratefully acknowledge funding via the Knut and Alice Wallenberg foundation(grant no.2019.0586)We thank Dr.Johannes Voss,Dr.Karun Kumar Rao and Dr.Benjamin Comer for fruitful discussions and acknowledge computational support from the National Energy Research Scientific Computing Center(computer time allocation m2997),a DOE Office of Science User Facility supported by the Office of Science of the U.S.Department of Energy under Contract No.DE-AC02-05CH11231.
文摘The chemisorption energy is an integral aspect of surface chemistry,central to numerous fields such as catalysis,corrosion,and nanotechnology.Electronic-structure-based methods such as the Newns-Anderson model are therefore of great importance in guiding the engineering of material surfaces with optimal properties.However,existing methods are inadequate for interpreting complex,multi-metallic systems.Herein,we introduce a physics-based chemisorption model for alloyed transition metal surfaces employing primarily metal d-band properties that accounts for perturbations in both the substrate and adsorbate electronic states upon interaction.Importantly,we show that adsorbate-induced changes in the adsorption site interact with its chemical environment leading to a second-order response in chemisorption energy with the d-filling of the neighboring atoms.We demonstrate the robustness of the model on a wide range of transition metal alloys with O,N,CH,and Li adsorbates yielding a mean absolute error of 0.13 eV versus density functional theory reference chemisorption energies.
