One disadvantage of direct anticoagulant drug is the lack of an antidote, which may become relevant in patients with traumatic brain in- jury. A 77-years old man with atrial fibrillation and syncope received dabigatra...One disadvantage of direct anticoagulant drug is the lack of an antidote, which may become relevant in patients with traumatic brain in- jury. A 77-years old man with atrial fibrillation and syncope received dabigatran despite recurrent falls. Due to a ground-level-fall, he suffered from subarachnoidal and intraparenchymal hemorrhages, subdural hematoma and brain edema with a midline shift. Despite osteoelast/c trepanation and hematoma-evacuation he remained comatose and died seven days later without regaining consciousness. Most probably, decreased dabigatran clearance due to increased age might have contributed to the fatal course. We suggest withholding anticoagulant therapy in patients with unexplained falls. If anticoagulant therapy is deemed necessary, vitamin-K-antagonists with their potential for laboratory monitoring and reversal of anticoagulant activity should be preferred.展开更多
Human epidermal growth factor receptor 2 （HER2） is over-expressed in 20%-25% of invasive breast cancer and is associated with an aggressive tumor phenotype and reduced survival rate. As a clinically widely applied H...Human epidermal growth factor receptor 2 （HER2） is over-expressed in 20%-25% of invasive breast cancer and is associated with an aggressive tumor phenotype and reduced survival rate. As a clinically widely applied HER2-targeted monoclonal antibody, trastuzumab （Herceptin）, combined with chemotherapy significantly increases the no tumor survival time of the patient. However, the majority of the cancers that initially respond to Herceptin begin to counter against the treat- ment within 1 year. This review describes several important well-known trastuzumab resistance mechanisms as well as the updated advancement in this field. The sufficiently investigated mechanisms are over-activation of PI3K/AKT pathway, activa- tion of PI3K/AKT via alternative pathway, steric hindrance of receptor-antibody interaction, increase of serum HER2 extracel- lular domain, and abnormal expression of epidermal growth factor receptor （EGFR） family and their ligands. And the newly investigated mechanisms involve Darpp-32 and t-Darpp, autophagy of tumor cells, HSP27, HsP90, c-MYC, ADAM proteases, EphA2, Racl, MUCI＊, HER2△16, and mesenchymal CD44（pos）CD24（neg/low） phenotype.展开更多
The henipaviruses,represented by Nipah virus and Hendra virus,are emerging zoonotic viral pathogens responsible for repeated outbreaks associated with high morbidity and mortality in Australia,Southeast Asia,India and...The henipaviruses,represented by Nipah virus and Hendra virus,are emerging zoonotic viral pathogens responsible for repeated outbreaks associated with high morbidity and mortality in Australia,Southeast Asia,India and Bangladesh. These viruses enter host cells via a class I viral fusion mechanism mediated by their attachment and fusion envelope glycoproteins;efficient membrane fusion requires both these glycoproteins in conjunction with specific virus receptors present on susceptible host cells. The henipavirus attachment glycoprotein interacts with a cellular B class ephrin protein receptor triggering conformational alterations leading to the activation of the viral fusion(F) glycoprotein. The analysis of monoclonal antibody(mAb) reactivity with G has revealed measurable alterations in the antigenic structure of the glycoprotein following its binding interaction with receptor. These observations only appear to occur with full-length native G glycoprotein,which is a tetrameric oligomer,and not with soluble forms of G(sG) ,which are disulfide-linked dimers. Single amino acid mutations in a heptad repeat-like structure within the stalk domain of G can disrupt its association with F and subsequent membrane fusion promotion activity. Notably,these mutants of G also appear to confer a post-receptor bound conformation implicating the stalk domain as an important element in the G glycoprotein's structure and functional relationship with F. Together,these observations suggest fusion is dependent on a specific interaction between the F and G glycoproteins of the henipaviruses. Further,receptor binding induces measurable changes in the G glycoprotein that appear to be greatest in respect to the interactions between the pairs of dimers comprising its native tetrameric structure. These receptor-induced conformational changes may be associated with the G glycoprotein's promotion of the fusion activity of F.展开更多
文摘One disadvantage of direct anticoagulant drug is the lack of an antidote, which may become relevant in patients with traumatic brain in- jury. A 77-years old man with atrial fibrillation and syncope received dabigatran despite recurrent falls. Due to a ground-level-fall, he suffered from subarachnoidal and intraparenchymal hemorrhages, subdural hematoma and brain edema with a midline shift. Despite osteoelast/c trepanation and hematoma-evacuation he remained comatose and died seven days later without regaining consciousness. Most probably, decreased dabigatran clearance due to increased age might have contributed to the fatal course. We suggest withholding anticoagulant therapy in patients with unexplained falls. If anticoagulant therapy is deemed necessary, vitamin-K-antagonists with their potential for laboratory monitoring and reversal of anticoagulant activity should be preferred.
文摘Human epidermal growth factor receptor 2 （HER2） is over-expressed in 20%-25% of invasive breast cancer and is associated with an aggressive tumor phenotype and reduced survival rate. As a clinically widely applied HER2-targeted monoclonal antibody, trastuzumab （Herceptin）, combined with chemotherapy significantly increases the no tumor survival time of the patient. However, the majority of the cancers that initially respond to Herceptin begin to counter against the treat- ment within 1 year. This review describes several important well-known trastuzumab resistance mechanisms as well as the updated advancement in this field. The sufficiently investigated mechanisms are over-activation of PI3K/AKT pathway, activa- tion of PI3K/AKT via alternative pathway, steric hindrance of receptor-antibody interaction, increase of serum HER2 extracel- lular domain, and abnormal expression of epidermal growth factor receptor （EGFR） family and their ligands. And the newly investigated mechanisms involve Darpp-32 and t-Darpp, autophagy of tumor cells, HSP27, HsP90, c-MYC, ADAM proteases, EphA2, Racl, MUCI＊, HER2△16, and mesenchymal CD44（pos）CD24（neg/low） phenotype.
基金supported in part by NIH grant AI054715 to C.C.B.
文摘The henipaviruses,represented by Nipah virus and Hendra virus,are emerging zoonotic viral pathogens responsible for repeated outbreaks associated with high morbidity and mortality in Australia,Southeast Asia,India and Bangladesh. These viruses enter host cells via a class I viral fusion mechanism mediated by their attachment and fusion envelope glycoproteins;efficient membrane fusion requires both these glycoproteins in conjunction with specific virus receptors present on susceptible host cells. The henipavirus attachment glycoprotein interacts with a cellular B class ephrin protein receptor triggering conformational alterations leading to the activation of the viral fusion(F) glycoprotein. The analysis of monoclonal antibody(mAb) reactivity with G has revealed measurable alterations in the antigenic structure of the glycoprotein following its binding interaction with receptor. These observations only appear to occur with full-length native G glycoprotein,which is a tetrameric oligomer,and not with soluble forms of G(sG) ,which are disulfide-linked dimers. Single amino acid mutations in a heptad repeat-like structure within the stalk domain of G can disrupt its association with F and subsequent membrane fusion promotion activity. Notably,these mutants of G also appear to confer a post-receptor bound conformation implicating the stalk domain as an important element in the G glycoprotein's structure and functional relationship with F. Together,these observations suggest fusion is dependent on a specific interaction between the F and G glycoproteins of the henipaviruses. Further,receptor binding induces measurable changes in the G glycoprotein that appear to be greatest in respect to the interactions between the pairs of dimers comprising its native tetrameric structure. These receptor-induced conformational changes may be associated with the G glycoprotein's promotion of the fusion activity of F.
