BACKGROUND Patients with paroxysmal nocturnal hemoglobinuria(PNH)have a clonal population of blood cells deficient in glycosylphosphatidylinositol-anchored(GPIanchored)proteins,most of the time resulting from a mutati...BACKGROUND Patients with paroxysmal nocturnal hemoglobinuria(PNH)have a clonal population of blood cells deficient in glycosylphosphatidylinositol-anchored(GPIanchored)proteins,most of the time resulting from a mutation in the X-linked gene PIGA.We report a patient with PNH resulting from a rare biallelic PIGT mutation on chromosome 20.CASE SUMMARY A 47-year-old man was referred to our hospital for febrile pancytopenia.The patient reported a history of recurrent urticaria and arthralgia and he presented during 3 mo recurrent acute dermo-hypodermitis and aseptic meningitidis.Based on clinical cases published with PIGT-PNH,with clinically typical PNH and autoinflammatory symptoms,we treated our patients with repeated infusions of eculizumab to decrease autoinflammatory symptoms and then we performed an allogeneic stem cell transplantation(allo-SCT)with a mismatched unrelated donor.Our patient experienced no acute Graft vs Host disease(GvHD)and a moderate chronic GvHD and is now considered cured at 24 mo after allo-SCT.CONCLUSION This case report suggests that allo-SCT should be considered to cure PIGT-PNH patients.展开更多
BACKGROUND Crohn’s disease(CD)is complicated by perianal fistulas in approximately 20%of patients.Achieving permanent fistula closure remains a challenge for physicians.An association between serum anti-tumor necrosi...BACKGROUND Crohn’s disease(CD)is complicated by perianal fistulas in approximately 20%of patients.Achieving permanent fistula closure remains a challenge for physicians.An association between serum anti-tumor necrosis factor-αconcentrations and clinical outcomes in patients with CD has been demonstrated;however,little information is available on serum adalimumab(ADA)concentrations and remission of perianal fistulas in such patients.AIM To study the relationship between serum ADA concentrations and clinical remission of CDassociated perianal fistulas.METHODS This cross-sectional study of patients with CD-associated perianal fistulas treated with ADA was performed at four French hospitals between December 2013 and March 2018.At the time of each serum ADA concentration measurement,we collected information about the patients and their fistulas.The primary study endpoint was clinical remission of fistulas defined as the absence of drainage(in accordance with Present’s criteria),with a PDAI≤4,absence of a seton and assessment of the overall evaluation as favorable by the proctologist at the relevant center.We also assessed fistula healing[defined as being in clinical and radiological(magnetic resonance imaging,MRI)remission]and adverse events.RESULTS The study cohort comprised 34 patients who underwent 56 evaluations(patients had between one and four evaluations).Fifteen patients had clinical remissions(44%),four of whom had healed fistulas on MRI.Serum ADA concentrations were significantly higher at evaluations in which clinical remission was identified than at evaluations in which it was not[14(10-16)vs 10(2-15)μg/mL,P=0.01].Serum ADA concentrations were comparable at the times of evaluation of patients with and without healed fistulas[11(7-14)vs 10(4-16)μg/mL,P=0.69].The adverse event rate did not differ between different serum ADA concentrations.CONCLUSION We found a significant association between high serum ADA concentrations and clinical remission of CD-associated perianal fistulas.展开更多
In this work, we have considered a new multimodality imaging for macroscopy based on Second Harmonic Generation (SHG) method to monitor invasivelessly the matrix collagen. As the triple helicoidally structure of colla...In this work, we have considered a new multimodality imaging for macroscopy based on Second Harmonic Generation (SHG) method to monitor invasivelessly the matrix collagen. As the triple helicoidally structure of collagen molecules appearing as not centrosymetric, very organized and spatially oriented, collagen fibrils give rise to a very strong SHG signal and can be imaged without any exogenous dye. To integrate a multidimensional scale with a large field of view (non-sliced samples), we have adapted and validated an instrumental coupling between a two photon excitation laser and a macroscope to collect cartography of SHG signal. We introduced an index (F-SHG) based on decay time response measured by TCSPC for respectively Fluorescence (F) and Second Harmonic Generation (SHG) values. For various sample where protein collagen is the major component of extracellular matrix (vessel, skin, carotide vessel, rat femoral head cartilage, mouse tumor, human wharton’s jelly and rat tendon) or not (nacre), we compared the index distribution obtained with MacroSHG. In this work, we showed for the first time that multiscale large field imaging (Macroscopy) combined to Multimodality approaches (SHG-TCSPC) could be an innovative and non-invasive technique to detect and identify some biological interest molecules (collagen) in biomedical topics.展开更多
The triggering receptor expressed on myeloid cells-1(TREM-1)is a receptor expressed on innate immune cells.By promoting the amplification of inflammatory signals that are initially triggered by Toll-like receptors(TLR...The triggering receptor expressed on myeloid cells-1(TREM-1)is a receptor expressed on innate immune cells.By promoting the amplification of inflammatory signals that are initially triggered by Toll-like receptors(TLRs),TREM-1 has been characterized as a major player in the pathophysiology of acute and chronic inflammatory diseases,such as septic shock,myocardial infarction,atherosclerosis,and inflammatory bowel diseases.However,the molecular events leading to the activation of TREM-1 in innate immune cells remain unknown.Here,we show that TREM-1 is activated by multimerization and that the levels of intracellular Ca 2+release,reactive oxygen species,and cytokine production correlate with the degree of TREM-1 aggregation.TREM-1 activation on primary human monocytes by LPS required a two-step process consisting of upregulation followed by clustering of TREM-1 at the cell surface,in contrast to primary human neutrophils,where LPS induced a rapid cell membrane reorganization of TREM-1,which confirmed that TREM-1 is regulated differently in primary human neutrophils and monocytes.In addition,we show that the ectodomain of TREM-1 is able to homooligomerize in a concentration-dependent manner,which suggests that the clustering of TREM-1 on the membrane promotes its oligomerization.We further show that the adapter protein DAP12 stabilizes TREM-1 surface expression and multimerization.TREM-1 multimerization at the cell surface is also mediated by its endogenous ligand,a conclusion supported by the ability of the TREM-1 inhibitor LR12 to limit TREM-1 multimerization.These results provide evidence for ligand-induced,receptor-mediated dimerization of TREM-1.Collectively,our findings uncover the mechanisms necessary for TREM-1 activation in monocytes and neutrophils.展开更多
Despite the exceptional progress in breast cancer pathogenesis,prognosis,diagnosis,and treatment strategies,it remains a prominent cause of female mortality worldwide.Additionally,although chemotherapies are effective...Despite the exceptional progress in breast cancer pathogenesis,prognosis,diagnosis,and treatment strategies,it remains a prominent cause of female mortality worldwide.Additionally,although chemotherapies are effective,they are associated with critical limitations,most notably their lack of specificity resulting in systemic toxicity and the eventual development of multi-drug resistance(MDR)cancer cells.Liposomes have proven to be an invaluable drug delivery system but of the multitudes of liposomal systems developed every year only a few have been approved for clinical use,none of which employ active targeting.In this review,we summarize the most recent strategies in development for actively targeted liposomal drug delivery systems for surface,transmembrane and internal cell receptors,enzymes,direct cell targeting and dual-targeting of breast cancer and breast cancer-associated cells,e.g.,cancer stem cells,cells associated with the tumor microenvironment,etc.展开更多
文摘BACKGROUND Patients with paroxysmal nocturnal hemoglobinuria(PNH)have a clonal population of blood cells deficient in glycosylphosphatidylinositol-anchored(GPIanchored)proteins,most of the time resulting from a mutation in the X-linked gene PIGA.We report a patient with PNH resulting from a rare biallelic PIGT mutation on chromosome 20.CASE SUMMARY A 47-year-old man was referred to our hospital for febrile pancytopenia.The patient reported a history of recurrent urticaria and arthralgia and he presented during 3 mo recurrent acute dermo-hypodermitis and aseptic meningitidis.Based on clinical cases published with PIGT-PNH,with clinically typical PNH and autoinflammatory symptoms,we treated our patients with repeated infusions of eculizumab to decrease autoinflammatory symptoms and then we performed an allogeneic stem cell transplantation(allo-SCT)with a mismatched unrelated donor.Our patient experienced no acute Graft vs Host disease(GvHD)and a moderate chronic GvHD and is now considered cured at 24 mo after allo-SCT.CONCLUSION This case report suggests that allo-SCT should be considered to cure PIGT-PNH patients.
基金Supported by the Assistance Publique des H?pitaux de Paris and AbbVie (North Chicago, Illinois, United States)
文摘BACKGROUND Crohn’s disease(CD)is complicated by perianal fistulas in approximately 20%of patients.Achieving permanent fistula closure remains a challenge for physicians.An association between serum anti-tumor necrosis factor-αconcentrations and clinical outcomes in patients with CD has been demonstrated;however,little information is available on serum adalimumab(ADA)concentrations and remission of perianal fistulas in such patients.AIM To study the relationship between serum ADA concentrations and clinical remission of CDassociated perianal fistulas.METHODS This cross-sectional study of patients with CD-associated perianal fistulas treated with ADA was performed at four French hospitals between December 2013 and March 2018.At the time of each serum ADA concentration measurement,we collected information about the patients and their fistulas.The primary study endpoint was clinical remission of fistulas defined as the absence of drainage(in accordance with Present’s criteria),with a PDAI≤4,absence of a seton and assessment of the overall evaluation as favorable by the proctologist at the relevant center.We also assessed fistula healing[defined as being in clinical and radiological(magnetic resonance imaging,MRI)remission]and adverse events.RESULTS The study cohort comprised 34 patients who underwent 56 evaluations(patients had between one and four evaluations).Fifteen patients had clinical remissions(44%),four of whom had healed fistulas on MRI.Serum ADA concentrations were significantly higher at evaluations in which clinical remission was identified than at evaluations in which it was not[14(10-16)vs 10(2-15)μg/mL,P=0.01].Serum ADA concentrations were comparable at the times of evaluation of patients with and without healed fistulas[11(7-14)vs 10(4-16)μg/mL,P=0.69].The adverse event rate did not differ between different serum ADA concentrations.CONCLUSION We found a significant association between high serum ADA concentrations and clinical remission of CD-associated perianal fistulas.
文摘In this work, we have considered a new multimodality imaging for macroscopy based on Second Harmonic Generation (SHG) method to monitor invasivelessly the matrix collagen. As the triple helicoidally structure of collagen molecules appearing as not centrosymetric, very organized and spatially oriented, collagen fibrils give rise to a very strong SHG signal and can be imaged without any exogenous dye. To integrate a multidimensional scale with a large field of view (non-sliced samples), we have adapted and validated an instrumental coupling between a two photon excitation laser and a macroscope to collect cartography of SHG signal. We introduced an index (F-SHG) based on decay time response measured by TCSPC for respectively Fluorescence (F) and Second Harmonic Generation (SHG) values. For various sample where protein collagen is the major component of extracellular matrix (vessel, skin, carotide vessel, rat femoral head cartilage, mouse tumor, human wharton’s jelly and rat tendon) or not (nacre), we compared the index distribution obtained with MacroSHG. In this work, we showed for the first time that multiscale large field imaging (Macroscopy) combined to Multimodality approaches (SHG-TCSPC) could be an innovative and non-invasive technique to detect and identify some biological interest molecules (collagen) in biomedical topics.
文摘The triggering receptor expressed on myeloid cells-1(TREM-1)is a receptor expressed on innate immune cells.By promoting the amplification of inflammatory signals that are initially triggered by Toll-like receptors(TLRs),TREM-1 has been characterized as a major player in the pathophysiology of acute and chronic inflammatory diseases,such as septic shock,myocardial infarction,atherosclerosis,and inflammatory bowel diseases.However,the molecular events leading to the activation of TREM-1 in innate immune cells remain unknown.Here,we show that TREM-1 is activated by multimerization and that the levels of intracellular Ca 2+release,reactive oxygen species,and cytokine production correlate with the degree of TREM-1 aggregation.TREM-1 activation on primary human monocytes by LPS required a two-step process consisting of upregulation followed by clustering of TREM-1 at the cell surface,in contrast to primary human neutrophils,where LPS induced a rapid cell membrane reorganization of TREM-1,which confirmed that TREM-1 is regulated differently in primary human neutrophils and monocytes.In addition,we show that the ectodomain of TREM-1 is able to homooligomerize in a concentration-dependent manner,which suggests that the clustering of TREM-1 on the membrane promotes its oligomerization.We further show that the adapter protein DAP12 stabilizes TREM-1 surface expression and multimerization.TREM-1 multimerization at the cell surface is also mediated by its endogenous ligand,a conclusion supported by the ability of the TREM-1 inhibitor LR12 to limit TREM-1 multimerization.These results provide evidence for ligand-induced,receptor-mediated dimerization of TREM-1.Collectively,our findings uncover the mechanisms necessary for TREM-1 activation in monocytes and neutrophils.
文摘Despite the exceptional progress in breast cancer pathogenesis,prognosis,diagnosis,and treatment strategies,it remains a prominent cause of female mortality worldwide.Additionally,although chemotherapies are effective,they are associated with critical limitations,most notably their lack of specificity resulting in systemic toxicity and the eventual development of multi-drug resistance(MDR)cancer cells.Liposomes have proven to be an invaluable drug delivery system but of the multitudes of liposomal systems developed every year only a few have been approved for clinical use,none of which employ active targeting.In this review,we summarize the most recent strategies in development for actively targeted liposomal drug delivery systems for surface,transmembrane and internal cell receptors,enzymes,direct cell targeting and dual-targeting of breast cancer and breast cancer-associated cells,e.g.,cancer stem cells,cells associated with the tumor microenvironment,etc.
