Degenerative disc disease(DDD) is associated with intervertebral disc degeneration of spinal instability. Here, we report that the cilia of nucleus pulposus(NP) cells mediate mechanotransduction to maintain anabolic a...Degenerative disc disease(DDD) is associated with intervertebral disc degeneration of spinal instability. Here, we report that the cilia of nucleus pulposus(NP) cells mediate mechanotransduction to maintain anabolic activity in the discs. We found that mechanical stress promotes transport of parathyroid hormone 1 receptor(PTH1 R) to the cilia and enhances parathyroid hormone(PTH) signaling in NP cells. PTH induces transcription of integrin α_vβ_6 to activate the transforming growth factor(TGF)-β-connective tissue growth factor(CCN2)-matrix proteins signaling cascade. Intermittent injection of PTH(iPTH) effectively attenuates disc degeneration of aged mice by direct signaling through NP cells, specifically improving intervertebral disc height and volume by increasing levels of TGF-β activity, CCN2, and aggrecan. PTH1 R is expressed in both mouse and human NP cells. Importantly,knockout PTH1 R or cilia in the NP cells results in significant disc degeneration and blunts the effect of PTH on attenuation of aged discs. Thus, mechanical stress-induced transport of PTH1 R to the cilia enhances PTH signaling, which helps maintain intervertebral disc homeostasis, particularly during aging, indicating therapeutic potential of iPTH for DDD.展开更多
Intervertebral disc （IVD） degeneration is the leading cause of disability with no disease-modifying treatment. IVD degeneration is associated with instable mechanical loading in the spine, but little is known about ...Intervertebral disc （IVD） degeneration is the leading cause of disability with no disease-modifying treatment. IVD degeneration is associated with instable mechanical loading in the spine, but little is known about how mechanical stress regulates nucleus notochordal （NC） cells to maintain IVD homeostasis. Here we report that mechanical stress can result in excessive integrin αvβ6-mediated activation of transforming growth factor beta （TGFβ）, decreased NC cell vacuoles, and increased matrix proteoglycan production, and results in degenerative disc disease （DDD）. Knockout of TGFβ type II receptor （TβRII） or integrin αv in the NC cells inhibited functional activity of postnatal NC cells and also resulted in DDD under mechanical loading. Administration of RGD peptide, TGFβ, and αvβ6-neutralizing antibodies attenuated IVD degeneration. Thus, integrin-mediated activation of TGFβ plays a critical role in mechanical signaling transduction to regulate IVD cell function and homeostasis. Manipulation of this signaling pathway may be a potential therapeutic target to modify DDD.展开更多
Cancer immunotherapy has finally joined the pillars of cancer treatment-surgery, radiation, chemotherapy, hormonal therapy, and targeted therapy-in improving cancer patient lives. In the last 5 years, the development ...Cancer immunotherapy has finally joined the pillars of cancer treatment-surgery, radiation, chemotherapy, hormonal therapy, and targeted therapy-in improving cancer patient lives. In the last 5 years, the development of immune checkpoint inhibitor and T cell therapy, particularly chimeric antigen receptor(CAR) T-cell therapy, has been remarkable for the speed, scale, and number of drug approvals. Still, these treatments may also bring unusual adverse effects and clinical outcomes including unprecedented long-term survival. Interrogating the tumor microenvironment and identifying better biomarkers hold the key to improving cancer immunotherapies. CAR T-cell therapy has dramatic effect on leukemias and lymphomas with significant cure rates, but has yet to show comparable effect on solid tumors. Cutting-edge technology will improve both processing and clinical effect of such therapies. Asia has the largest, most rapidly aging population and the largest number of cancer patients in the world. Research and development and clinical trial conduct of cancer immunotherapy in Asia remain nascent, but should be a crucial priority.展开更多
As patients with carcinoma of the esophagus live longer, complications associated with the use of a gastric conduit are increasing. Ulcers form in the gastric conduit in 6.6% to 19.4% of patients. There are a few repo...As patients with carcinoma of the esophagus live longer, complications associated with the use of a gastric conduit are increasing. Ulcers form in the gastric conduit in 6.6% to 19.4% of patients. There are a few reports of perforation of a gastric conduit in the English literature. Almost all of these were associated with serious complications. We report a patient who developed a tension pneumothorax consequent to spontaneous perforation of an ulcer in the gastric conduit 7 years after the index surgery in a patient with carcinoma of the gastroesophageal junction. He responded well to conservative management. Complications related to a gastric conduit can be because of multiple factors. Periodic endoscopic surveillance of gastric conduits should be considered as these are at a higher risk of ulcer formation than a normal stomach. Long term treatment with proton pump inhibitors may decrease complications. There are no guidelines for the treatment of a perforated gastric conduit ulcer and the management should be individualized.展开更多
Plastic scintillation detectors based whole body β/γ contamination monitors are developed for use in radiation facilities.This microcontroller-based multi-detector system uses 13 plastic scintillator detectors,with ...Plastic scintillation detectors based whole body β/γ contamination monitors are developed for use in radiation facilities.This microcontroller-based multi-detector system uses 13 plastic scintillator detectors,with minimized dead detection zones,monitoring the whole body,and conforming to the contamination limit prescribed by the regulatory authority.This system has the features for monitoring hands,feet,head,and faceβ/γusing contamination monitors and portal exit monitors.It can detect gamma sources at a dose rate of 10 n Gyh^(-1).The system is calibrated using b sources^(90)Sr/^(90)Y,^(204)Tl,and^(36)Cl,and the efficiency is found to be 29%,22%,and 18%,respectively.Theminimumdetectableβ/γcontaminationis0.15 Bqcm^(-2),which is significantly less than the minimum detection objectives on head,face,hands,and feet.展开更多
In this era of fast-depleting natural resources,the hike in fuel prices is ever-growing.With stringent norms over environmental policies,the automotive manufacturers are on a voyage to produce efficient vehicles with ...In this era of fast-depleting natural resources,the hike in fuel prices is ever-growing.With stringent norms over environmental policies,the automotive manufacturers are on a voyage to produce efficient vehicles with lower emissions.High-speed cars are at a stake to provide uncompromised performance but having strict rules over emissions drives the companies to approach through a different route to keep the demands of performance intact.One of the most sought-after ways is to improve the aerodynamics of the vehicles.Drag force is one of the major setbacks when it comes to achieving high speeds when the vehicle is in motion.This research aims to examine the effects of different add on devices on the vehicle to reduce drag and make the vehicle aerodynamically streamlined.A more streamlined vehicle will be able to achieve high speeds and consequently,the fuel economy is also improved.The three-dimensional car model is developed in SOLIDWORKS v17.Computational Fluid Dynamics(CFD)is performed to understand the effects of these add on devices.CFD is carried out in the ANSYS^(TM) 17.0 Fluent module.Drag Coefficient(CD),Lift Coefficient(CL),Drag Force and Lift Force are calculated and compared in different cases.The result of the simulations was analyzed and it was observed that different devices posed several different functionalities,but maximum drag reduction was found in the case of GT with spoiler and diffuser with a maximum reduction of 16.53%.展开更多
Background Plastic scintillator detectors are rugged and easily manufactured in desired shape,sizes and response time to gamma radiation is prompt as compared with any other scintillator detectors.Being popular these ...Background Plastic scintillator detectors are rugged and easily manufactured in desired shape,sizes and response time to gamma radiation is prompt as compared with any other scintillator detectors.Being popular these detectors are used in radiation monitors one of the application to restrict radioactive material movement.These are used in gross counting mode to know the presence of radioactivity.Therefore secondary survey is required to know the nature of the radionuclides.Purpose The feasibility study of Cylindrical Plastic Scintillator Detector(CPSD)was carried out for the qualitative and quantitative assessment of gamma emitting radionuclides.Methods In this work limited gamma spectrometry was carried out using NE110 equivalent cylindrical plastic scintillating material of 5.1 cm diameter and 100 cm long.CPSD is optically coupled to photomultiplier tube(PMT).The detector signal is processed using preamplifier,shaping amplifier and further analysed by a multi channel analyser(MCA).CPSD gamma spectrum consists of Compton continuum and Gaussian shaped Compton edge energy(λ_(e))appearing as Compton maxima energy(λ_(max)).Photon transport simulation is used to characterizeλ_(max) as a signature for radionuclides emitting gamma energy/energies.In case of unresolved gamma energies,it appears as weighted effective Compton maxima energy.The prominent gamma energies observed across nuclear industries are in the energy range 0.03–3 MeV.It is grouped as low energy,intermediate energy,high energy and ultra-high energy window.The simulated spectrum is obtained suing Gaussian broadening parameters deduced from experimentally measured spectrum.The efficiency response function is developed from simulated response of detector to standard gamma sources under known source detector configurations.Results The mono energetic gamma emitting radioisotopes are identified againstλ_(max) from data library.Qualitative analysis of spectrum is used to discriminate artificial radioactive material from naturally occurring radioactive material using gamma photon,corresponding Compton edge and expected Compton maxima in each energy window.The provisional quantitative assessment is carried out using efficiency deduced from response function.The detection efficiency varies within 1%–0.2%for 0.03 to 3 MeV gamma energies.In this study efficiency for ^(137)Cs source is 0.26%with FWHM 0.092 MeV and the results re within 15%for the measured activity.Estimated sensitivity and spectral dose rate coefficient for CPSD are 77 cps/µR/h and 44.29 nGy/kcps respectively.The MDA or MDL of the most prominent radioisotopes used in nuclear industry are estimated.CPSD showed an ability to detect 149 kBq,^(137)Cs radioisotope at 1 m distance.Conclusion CPSD can be utilised for gamma isotope identification with limited gamma spectroscopy tool in contamination and dose rate measurements monitors.展开更多
基金supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under Award Numbers AR071432 and AR063943
文摘Degenerative disc disease(DDD) is associated with intervertebral disc degeneration of spinal instability. Here, we report that the cilia of nucleus pulposus(NP) cells mediate mechanotransduction to maintain anabolic activity in the discs. We found that mechanical stress promotes transport of parathyroid hormone 1 receptor(PTH1 R) to the cilia and enhances parathyroid hormone(PTH) signaling in NP cells. PTH induces transcription of integrin α_vβ_6 to activate the transforming growth factor(TGF)-β-connective tissue growth factor(CCN2)-matrix proteins signaling cascade. Intermittent injection of PTH(iPTH) effectively attenuates disc degeneration of aged mice by direct signaling through NP cells, specifically improving intervertebral disc height and volume by increasing levels of TGF-β activity, CCN2, and aggrecan. PTH1 R is expressed in both mouse and human NP cells. Importantly,knockout PTH1 R or cilia in the NP cells results in significant disc degeneration and blunts the effect of PTH on attenuation of aged discs. Thus, mechanical stress-induced transport of PTH1 R to the cilia enhances PTH signaling, which helps maintain intervertebral disc homeostasis, particularly during aging, indicating therapeutic potential of iPTH for DDD.
文摘Intervertebral disc （IVD） degeneration is the leading cause of disability with no disease-modifying treatment. IVD degeneration is associated with instable mechanical loading in the spine, but little is known about how mechanical stress regulates nucleus notochordal （NC） cells to maintain IVD homeostasis. Here we report that mechanical stress can result in excessive integrin αvβ6-mediated activation of transforming growth factor beta （TGFβ）, decreased NC cell vacuoles, and increased matrix proteoglycan production, and results in degenerative disc disease （DDD）. Knockout of TGFβ type II receptor （TβRII） or integrin αv in the NC cells inhibited functional activity of postnatal NC cells and also resulted in DDD under mechanical loading. Administration of RGD peptide, TGFβ, and αvβ6-neutralizing antibodies attenuated IVD degeneration. Thus, integrin-mediated activation of TGFβ plays a critical role in mechanical signaling transduction to regulate IVD cell function and homeostasis. Manipulation of this signaling pathway may be a potential therapeutic target to modify DDD.
文摘Cancer immunotherapy has finally joined the pillars of cancer treatment-surgery, radiation, chemotherapy, hormonal therapy, and targeted therapy-in improving cancer patient lives. In the last 5 years, the development of immune checkpoint inhibitor and T cell therapy, particularly chimeric antigen receptor(CAR) T-cell therapy, has been remarkable for the speed, scale, and number of drug approvals. Still, these treatments may also bring unusual adverse effects and clinical outcomes including unprecedented long-term survival. Interrogating the tumor microenvironment and identifying better biomarkers hold the key to improving cancer immunotherapies. CAR T-cell therapy has dramatic effect on leukemias and lymphomas with significant cure rates, but has yet to show comparable effect on solid tumors. Cutting-edge technology will improve both processing and clinical effect of such therapies. Asia has the largest, most rapidly aging population and the largest number of cancer patients in the world. Research and development and clinical trial conduct of cancer immunotherapy in Asia remain nascent, but should be a crucial priority.
文摘As patients with carcinoma of the esophagus live longer, complications associated with the use of a gastric conduit are increasing. Ulcers form in the gastric conduit in 6.6% to 19.4% of patients. There are a few reports of perforation of a gastric conduit in the English literature. Almost all of these were associated with serious complications. We report a patient who developed a tension pneumothorax consequent to spontaneous perforation of an ulcer in the gastric conduit 7 years after the index surgery in a patient with carcinoma of the gastroesophageal junction. He responded well to conservative management. Complications related to a gastric conduit can be because of multiple factors. Periodic endoscopic surveillance of gastric conduits should be considered as these are at a higher risk of ulcer formation than a normal stomach. Long term treatment with proton pump inhibitors may decrease complications. There are no guidelines for the treatment of a perforated gastric conduit ulcer and the management should be individualized.
文摘Plastic scintillation detectors based whole body β/γ contamination monitors are developed for use in radiation facilities.This microcontroller-based multi-detector system uses 13 plastic scintillator detectors,with minimized dead detection zones,monitoring the whole body,and conforming to the contamination limit prescribed by the regulatory authority.This system has the features for monitoring hands,feet,head,and faceβ/γusing contamination monitors and portal exit monitors.It can detect gamma sources at a dose rate of 10 n Gyh^(-1).The system is calibrated using b sources^(90)Sr/^(90)Y,^(204)Tl,and^(36)Cl,and the efficiency is found to be 29%,22%,and 18%,respectively.Theminimumdetectableβ/γcontaminationis0.15 Bqcm^(-2),which is significantly less than the minimum detection objectives on head,face,hands,and feet.
文摘In this era of fast-depleting natural resources,the hike in fuel prices is ever-growing.With stringent norms over environmental policies,the automotive manufacturers are on a voyage to produce efficient vehicles with lower emissions.High-speed cars are at a stake to provide uncompromised performance but having strict rules over emissions drives the companies to approach through a different route to keep the demands of performance intact.One of the most sought-after ways is to improve the aerodynamics of the vehicles.Drag force is one of the major setbacks when it comes to achieving high speeds when the vehicle is in motion.This research aims to examine the effects of different add on devices on the vehicle to reduce drag and make the vehicle aerodynamically streamlined.A more streamlined vehicle will be able to achieve high speeds and consequently,the fuel economy is also improved.The three-dimensional car model is developed in SOLIDWORKS v17.Computational Fluid Dynamics(CFD)is performed to understand the effects of these add on devices.CFD is carried out in the ANSYS^(TM) 17.0 Fluent module.Drag Coefficient(CD),Lift Coefficient(CL),Drag Force and Lift Force are calculated and compared in different cases.The result of the simulations was analyzed and it was observed that different devices posed several different functionalities,but maximum drag reduction was found in the case of GT with spoiler and diffuser with a maximum reduction of 16.53%.
文摘Background Plastic scintillator detectors are rugged and easily manufactured in desired shape,sizes and response time to gamma radiation is prompt as compared with any other scintillator detectors.Being popular these detectors are used in radiation monitors one of the application to restrict radioactive material movement.These are used in gross counting mode to know the presence of radioactivity.Therefore secondary survey is required to know the nature of the radionuclides.Purpose The feasibility study of Cylindrical Plastic Scintillator Detector(CPSD)was carried out for the qualitative and quantitative assessment of gamma emitting radionuclides.Methods In this work limited gamma spectrometry was carried out using NE110 equivalent cylindrical plastic scintillating material of 5.1 cm diameter and 100 cm long.CPSD is optically coupled to photomultiplier tube(PMT).The detector signal is processed using preamplifier,shaping amplifier and further analysed by a multi channel analyser(MCA).CPSD gamma spectrum consists of Compton continuum and Gaussian shaped Compton edge energy(λ_(e))appearing as Compton maxima energy(λ_(max)).Photon transport simulation is used to characterizeλ_(max) as a signature for radionuclides emitting gamma energy/energies.In case of unresolved gamma energies,it appears as weighted effective Compton maxima energy.The prominent gamma energies observed across nuclear industries are in the energy range 0.03–3 MeV.It is grouped as low energy,intermediate energy,high energy and ultra-high energy window.The simulated spectrum is obtained suing Gaussian broadening parameters deduced from experimentally measured spectrum.The efficiency response function is developed from simulated response of detector to standard gamma sources under known source detector configurations.Results The mono energetic gamma emitting radioisotopes are identified againstλ_(max) from data library.Qualitative analysis of spectrum is used to discriminate artificial radioactive material from naturally occurring radioactive material using gamma photon,corresponding Compton edge and expected Compton maxima in each energy window.The provisional quantitative assessment is carried out using efficiency deduced from response function.The detection efficiency varies within 1%–0.2%for 0.03 to 3 MeV gamma energies.In this study efficiency for ^(137)Cs source is 0.26%with FWHM 0.092 MeV and the results re within 15%for the measured activity.Estimated sensitivity and spectral dose rate coefficient for CPSD are 77 cps/µR/h and 44.29 nGy/kcps respectively.The MDA or MDL of the most prominent radioisotopes used in nuclear industry are estimated.CPSD showed an ability to detect 149 kBq,^(137)Cs radioisotope at 1 m distance.Conclusion CPSD can be utilised for gamma isotope identification with limited gamma spectroscopy tool in contamination and dose rate measurements monitors.
