Since its initial description in 1964,research hastransformed spontaneous bacterial peritonitis (SBP)from a feared disease (with reported mortality of 90%)to a treatable complication of decompensated cirrhosis,albeit ...Since its initial description in 1964,research hastransformed spontaneous bacterial peritonitis (SBP)from a feared disease (with reported mortality of 90%)to a treatable complication of decompensated cirrhosis,albeit with steady prevalence and a high recurrencerate. Bacterial translocation,the key mechanism in thepathogenesis of SBP,is only possible because of theconcurrent failure of defensive mechanisms in cirrhosis.Variants of SBP should be treated. Leucocyte esterasereagent strips have managed to shorten the 'tap-to-shot' time,while future studies should look into theircombined use with ascitic fluid pH. Third generationcephalosporins are the antibiotic of choice becausethey have a number of advantages. Renal dysfunctionhas been shown to be an independent predictor ofmortality in patients with SBP. Albumin is felt to reducethe risk of renal impairment by improving effectiveintravascular volume,and by helping to bind pro-inflammatory molecules. Following a single episodeof SBP,patients should have long-term antibioticprophylaxis and be considered for liver transplantation.展开更多
Recent studies have suggested an involvement of processing pathways for the initiation of cellular responses induced by topoisomerase-targeting drugs. Here, we showed that cellular exposure to camptothecin （CPT） ind...Recent studies have suggested an involvement of processing pathways for the initiation of cellular responses induced by topoisomerase-targeting drugs. Here, we showed that cellular exposure to camptothecin （CPT） induced formation of topoisomerase I cleavable complex （TOPlcc）, degradation of TOP1 and activation of DNA damage responses （DDR）. Transcription and proteasome-dependent proteolysis, but not replication, were involved in CPTo indneed TOPl degradation, while none of above three processing activities affected TOPlcc formation. Replication- and transcription-initiated proeessing （RIP and TIP） of TOPlee were identified as two independent pathways, which contribute distinctly to various CPT-activated DDR. Specifically, in cycling cells, RIP-processed TOPlec triggered the CPT-induced RPA pbosphorylation. At higher CPT dosages, the TIP pathway is required for other DDR activation, including ATM, p53 and Chkl/2 phosphorylation. The TIP pathway was further demonstrated to be S-phase independent by using three nonreplicating cell models. Furthermore, the effect of proteasome inhibitors mimicked that of transcription inhibition on the CPT-induced activation of DDR, suggesting the involvement of proteasome in the TIP pathway. Interestingly, the TIP pathway was important for TOPlcc-activated, but not ionization radiationactivated ATM, p53 and Chk2 phosphorylation. We have also found that pharmacological interferences of TIP and RIP pathways distinctively modulated the CPT-induced cell killing with treatments at low and high dosages, respec- tively. Together, our results support that both RIP and TIP pathways of TOPlcc are required for the activation of CPT-induced DDR and cytotoxicity.展开更多
文摘Since its initial description in 1964,research hastransformed spontaneous bacterial peritonitis (SBP)from a feared disease (with reported mortality of 90%)to a treatable complication of decompensated cirrhosis,albeit with steady prevalence and a high recurrencerate. Bacterial translocation,the key mechanism in thepathogenesis of SBP,is only possible because of theconcurrent failure of defensive mechanisms in cirrhosis.Variants of SBP should be treated. Leucocyte esterasereagent strips have managed to shorten the 'tap-to-shot' time,while future studies should look into theircombined use with ascitic fluid pH. Third generationcephalosporins are the antibiotic of choice becausethey have a number of advantages. Renal dysfunctionhas been shown to be an independent predictor ofmortality in patients with SBP. Albumin is felt to reducethe risk of renal impairment by improving effectiveintravascular volume,and by helping to bind pro-inflammatory molecules. Following a single episodeof SBP,patients should have long-term antibioticprophylaxis and be considered for liver transplantation.
文摘Recent studies have suggested an involvement of processing pathways for the initiation of cellular responses induced by topoisomerase-targeting drugs. Here, we showed that cellular exposure to camptothecin （CPT） induced formation of topoisomerase I cleavable complex （TOPlcc）, degradation of TOP1 and activation of DNA damage responses （DDR）. Transcription and proteasome-dependent proteolysis, but not replication, were involved in CPTo indneed TOPl degradation, while none of above three processing activities affected TOPlcc formation. Replication- and transcription-initiated proeessing （RIP and TIP） of TOPlee were identified as two independent pathways, which contribute distinctly to various CPT-activated DDR. Specifically, in cycling cells, RIP-processed TOPlec triggered the CPT-induced RPA pbosphorylation. At higher CPT dosages, the TIP pathway is required for other DDR activation, including ATM, p53 and Chkl/2 phosphorylation. The TIP pathway was further demonstrated to be S-phase independent by using three nonreplicating cell models. Furthermore, the effect of proteasome inhibitors mimicked that of transcription inhibition on the CPT-induced activation of DDR, suggesting the involvement of proteasome in the TIP pathway. Interestingly, the TIP pathway was important for TOPlcc-activated, but not ionization radiationactivated ATM, p53 and Chk2 phosphorylation. We have also found that pharmacological interferences of TIP and RIP pathways distinctively modulated the CPT-induced cell killing with treatments at low and high dosages, respec- tively. Together, our results support that both RIP and TIP pathways of TOPlcc are required for the activation of CPT-induced DDR and cytotoxicity.
