Pancreatic cancer has become the fourth leading cause of cancer death in the last two decades. Only 3%-15% of patients diagnosed with pancreatic cancer had 5 year survival rate. Drug resistance, high metastasis, poor ...Pancreatic cancer has become the fourth leading cause of cancer death in the last two decades. Only 3%-15% of patients diagnosed with pancreatic cancer had 5 year survival rate. Drug resistance, high metastasis, poor prognosis and tumour relapse contributed to the malignancies and difficulties in treating pancreatic cancer. The current standard chemotherapy for pancreatic cancer is gemcitabine, however its efficacy is far from satisfactory, one of the reasons is due to the complex tumour microenvironment which decreases effective drug delivery to target cancer cell. Studies of the molecular pathology of pancreatic cancer have revealed that activation of KRAS, overexpression of cyclooxygenase-2, inactivation of p16<sup>INK4A</sup> and loss of p53 activities occurred in pancreatic cancer. Co-administration of gemcitabine and targeting the molecular pathological events happened in pancreatic cancer has brought an enhanced therapeutic effectiveness of gemcitabine. Therefore, studies looking for novel targets in hindering pancreatic tumour growth are emerging rapidly. In order to give a better understanding of the current findings and to seek the direction in future pancreatic cancer research; in this review we will focus on targets suppressing tumour metastatsis and progression, KRAS activated downstream effectors, the relationship of Notch signaling and Nodal/Activin signaling with pancreatic cancer cells, the current findings of non-coding RNAs in inhibiting pancreatic cancer cell proliferation, brief discussion in transcription remodeling by epigenetic modifiers (e.g., HDAC, BMI1, EZH2) and the plausible therapeutic applications of cancer stem cell and hyaluronan in tumour environment.展开更多
Accelerated forgetting has been identified as a feature of Alzheimer's disease(AD),but the therapeutic efficacy of the manipulation of biological mechanisms of forgetting has not been assessed in AD animal models....Accelerated forgetting has been identified as a feature of Alzheimer's disease(AD),but the therapeutic efficacy of the manipulation of biological mechanisms of forgetting has not been assessed in AD animal models.Ras-re-lated C3 botulinum toxin substrate 1(Rac1),a small GTPase,has been shown to regulate active forgetting in Drosophila and mice?Here,we showed that Rac1 activity is aberrantly elevated in the hippocampal tissues of AD patients and AD animal models.Moreover,amyloid-beta 42 could induce Rac1 activation in cultured cells.The elevation of Rac1 activity not only accelerated 6-hour spatial memory decay in 3-month-old APP/PS1 mice,but also significantly contributed to severe memory loss in aged APP/PS1 mice.A similar age-dependent Rac1 activity-based memory loss was also observed in an AD fly model.Moreover,inhibition of Rac1 activity could ameliorate cognitive defects and synaptic plasticity in AD animal models.Finally,two novel compounds,identified through behavioral screening of a randomly selected pool of brain permeable small molecules for their positive effect in rescuing memory loss in both fly and mouse models,were found to be capable of inhibiting Rac1 activity.Thus,multiple lines of evidence corroborate in supporting the idea that inhibition of Rac1 activity is effective for treating AD-related memory loss.展开更多
文摘Pancreatic cancer has become the fourth leading cause of cancer death in the last two decades. Only 3%-15% of patients diagnosed with pancreatic cancer had 5 year survival rate. Drug resistance, high metastasis, poor prognosis and tumour relapse contributed to the malignancies and difficulties in treating pancreatic cancer. The current standard chemotherapy for pancreatic cancer is gemcitabine, however its efficacy is far from satisfactory, one of the reasons is due to the complex tumour microenvironment which decreases effective drug delivery to target cancer cell. Studies of the molecular pathology of pancreatic cancer have revealed that activation of KRAS, overexpression of cyclooxygenase-2, inactivation of p16<sup>INK4A</sup> and loss of p53 activities occurred in pancreatic cancer. Co-administration of gemcitabine and targeting the molecular pathological events happened in pancreatic cancer has brought an enhanced therapeutic effectiveness of gemcitabine. Therefore, studies looking for novel targets in hindering pancreatic tumour growth are emerging rapidly. In order to give a better understanding of the current findings and to seek the direction in future pancreatic cancer research; in this review we will focus on targets suppressing tumour metastatsis and progression, KRAS activated downstream effectors, the relationship of Notch signaling and Nodal/Activin signaling with pancreatic cancer cells, the current findings of non-coding RNAs in inhibiting pancreatic cancer cell proliferation, brief discussion in transcription remodeling by epigenetic modifiers (e.g., HDAC, BMI1, EZH2) and the plausible therapeutic applications of cancer stem cell and hyaluronan in tumour environment.
文摘Accelerated forgetting has been identified as a feature of Alzheimer's disease(AD),but the therapeutic efficacy of the manipulation of biological mechanisms of forgetting has not been assessed in AD animal models.Ras-re-lated C3 botulinum toxin substrate 1(Rac1),a small GTPase,has been shown to regulate active forgetting in Drosophila and mice?Here,we showed that Rac1 activity is aberrantly elevated in the hippocampal tissues of AD patients and AD animal models.Moreover,amyloid-beta 42 could induce Rac1 activation in cultured cells.The elevation of Rac1 activity not only accelerated 6-hour spatial memory decay in 3-month-old APP/PS1 mice,but also significantly contributed to severe memory loss in aged APP/PS1 mice.A similar age-dependent Rac1 activity-based memory loss was also observed in an AD fly model.Moreover,inhibition of Rac1 activity could ameliorate cognitive defects and synaptic plasticity in AD animal models.Finally,two novel compounds,identified through behavioral screening of a randomly selected pool of brain permeable small molecules for their positive effect in rescuing memory loss in both fly and mouse models,were found to be capable of inhibiting Rac1 activity.Thus,multiple lines of evidence corroborate in supporting the idea that inhibition of Rac1 activity is effective for treating AD-related memory loss.
