It is increasingly clear that interindividual variability in human gut microbial composition contributes to differential drug responses. For example, gastrointestinal (GI) toxicity is not observed in ...all patients treated with the anticancer drug irinotecan, and it has been suggested that this variability is a result of differences in the types and levels of gut bacterial β-glucuronidases (GUSs). GUS enzymes promote drug toxicity by hydrolyzing the inactive drug–glucuronide conjugate back to the active drug, which damages the GI epithelium. Proteomics-based identification of the exact GUS enzymes responsible for drug reactivation from the complexity of the human microbiota has not been accomplished, however. Here, we discover the specific bacterial GUS enzymes that generate SN-38, the active and toxic metabolite of irinotecan, from human fecal samples using a unique activity-based protein profiling (ABPP) platform. We identify and quantify gut bacterial GUS enzymes from human feces with an ABPP-enabled proteomics pipeline and then integrate this information with ex vivo kinetics to pinpoint the specific GUS enzymes responsible for SN-38 reactivation. Furthermore, the same approach also reveals the molecular basis for differential gut bacterial GUS inhibition observed between human fecal samples. Taken together, this work provides an unprecedented technical and bioinformatics pipeline to discover the microbial enzymes responsible for specific reactions from the complexity of human feces. Identifying such microbial enzymes may lead to precision biomarkers and novel drug targets to advance the promise of personalized medicine.
Childhood interstitial and diffuse lung disease (chILD) encompasses a broad spectrum of rare disorders. The Children's Interstitial and Diffuse Lung Disease Research Network (chILDRN) established a ...prospective registry to advance knowledge regarding etiology, phenotype, natural history, and management of these disorders.
This longitudinal, observational, multicenter registry utilizes single-IRB reliance agreements, with participation from 25 chILDRN centers across the U.S. Clinical data are collected and managed using the Research Electronic Data Capture (REDCap) electronic data platform.
We report the study design and selected elements of the initial Registry enrollment cohort, which includes 683 subjects with a broad range of chILD diagnoses. The most common diagnosis reported was neuroendocrine cell hyperplasia of infancy, with 155 (23%) subjects. Components of underlying disease biology were identified by enrolling sites, with cohorts of interstitial fibrosis, immune dysregulation, and airway disease being most commonly reported. Prominent morbidities affecting enrolled children included home supplemental oxygen use (63%) and failure to thrive (46%).
This Registry is the largest longitudinal chILD cohort in the United States to date, providing a powerful framework for collaborating centers committed to improving the understanding and treatment of these rare disorders.
Risk factors, morbidity and mortality from pulmonary fungal infections (PFIs) within the first year after pediatric lung transplant have not previously been characterized.
A retrospective, ...multicenter study from 1988 to 2005 was conducted with institutional approval from the 12 participating centers in North America and Europe. Data were recorded for the first post-transplant year. The log-rank test assessed for the association between PFI and survival. Associations between time to PFI and risk factors were assessed by Cox proportional hazards models.
Of the 555 subjects transplanted, 58 (10.5%) had 62 proven (Candida, Aspergillus or other) or probable (Aspergillus or other) PFIs within the first year post-transplant. The mean age for PFI subjects was 14.0 years vs 11.4 years for non-PFI subjects (p < 0.01). Candida and Aspergillus species were recovered equally for proven disease. Comparing subjects with PFI (n = 58) vs those without (n = 404), pre-transplant colonization was associated with PFI (hazard ratio HR 2.0; 95% CI 0.95 to 4.3, p = 0.067). Cytomegalovirus (CMV) mismatch, tacrolimus-based regimen and age >15 years were associated with PFI (p < 0.05). PFI was associated with any prior rejection higher than Grade A2 (HR 2.1; 95% CI 1.2 to 3.6). Cystic fibrosis, induction therapy, transplant era and type of transplant were not associated with PFI. PFI was independently associated with decreased 12-month survival (HR 3.9, 95% CI 2.2 to 6.8).
Risk factors for PFI include Grade A2 rejection, repeated acute rejection, CMV-positive donor, tacrolimus-based regimen and pre-transplant colonization.
A retrospective review of pediatric lung transplant recipients at 14 centers in North America and Europe was conducted to characterize the epidemiology and the risk factors for cytomegalovirus (CMV) ...and to explore the impact of preventative antiviral therapy.
Data were recorded for 1 year posttransplant. Associations between CMV and continuous and categorical risk factors were assessed using Wilcoxon rank sum and chi-square tests, respectively. Associations between time to CMV and risk factors or survival were assessed by multivariable Cox proportional hazards models.
Within 12 months posttransplant, 172 of 577 subjects (29.8%) developed 218 CMV episodes (90 asymptomatic infection, 25 syndrome, and 103 disease). Forty-one subjects developed more than one episode of CMV. Donor or recipient CMV seropositivity was associated with increased risk of CMV episodes. Except for decreased prophylaxis in CMV D-/R- subjects, duration of prophylaxis did not vary by D/R serostatus. For CMV D+ subjects, not being on prophylaxis at the time of CMV episode increased the risk of CMV (D+/R+ hazard ratio 3.5, 95% confidence interval 1.4-8.4; D+/R- 1.9, 1.02-3.7). CMV was associated with increased mortality within the first posttransplant year among those with donor or recipient CMV seropositivity (hazard ratio 2.0: 95% confidence interval 1.1-3.6; P=0.024).
CMV remains a serious complication after pediatric lung transplant, and the impact of prophylaxis is complex.
Pulmonary complications are frequently seen in survivors of childhood cancer, and are due to both disease-related and treatment-related causes. While primary lung cancer is extremely rare in the ...pediatric population, the lung is a common site for metastatic disease. Furthermore, therapies used to treat the pediatric population can often cause pulmonary toxicity. Specifically, chemotherapy, radiation, hematopoietic stem cell transplant, and surgery can all cause long-term damage to the sensitive lung tissue. These pulmonary sequelae can be further subdivided into acute and late effects.
To assess the efficacy and safety of the removal of pancreatic duct stones by a combined modality approach in patients with pancreatic ductal lithiasis and recurrent abdominal pain.
Retrospective ...review with a mean follow-up of 19 months (range, 1 to 56 months).
A tertiary care, private community hospital with a university affiliation.
The records of patients who presented to the hospital or who were referred with recurrent abdominal pain and who were demonstrated to have pancreatic ductal lithiasis between 1989 and 1994 were reviewed. Patients were assessed by their clinical response to pancreatic duct stone extraction by a variety of therapeutic interventions.
Fifteen patients were included in the study. One patient was excluded from analysis because of a concurrent choledochocele. Two patients required operative decompression and stone extraction for endoscopically inaccessible stones. Six patients were treated with endoscopic management alone, and six were treated with a combination of extracorporeal shock wave lithotripsy and endoscopic stone retrieval. Twelve patients had complete clearance of the pancreatic duct. One patient had a stone that was not removed, but adequate pancreatic ductal decompression was achieved. The remaining patient had incomplete clearance of pancreatic stone fragments following extracorporeal shock wave lithotripsy but had adequate ductal drainage. No patient has required further therapy or hospitalization for abdominal pain. No complications occurred as a result of any intervention in this study.
A multidisciplinary combined modality approach is a safe and effective method for extracting pancreatic duct stones in symptomatic patients. Stone extraction and reestablishment of adequate ductal drainage appear to relieve symptoms in some patients.
Cytomegalovirus (CMV) has been associated with morbidity, including chronic allograft rejection, in transplant recipients. Data from adult centers suggests that CMV hyperimmune globulin (CMVIG) and ...ganciclovir together are superior in preventing CMV viremia than ganciclovir alone.
A retrospective review of pediatric lung transplant recipients at 14 sites in North America and Europe was conducted to evaluate the effect of adding cytomegalovirus immunoglobulin (CMVIG) prophylaxis to at least 3 weeks of intravenous ganciclovir therapy in pediatric lung transplant recipients. Data were recorded for the first year after transplantation. Associations between time to CMV and risk factors, including CMVIG use, were assessed by multivariable Cox proportional hazards models.
Of 599 patients whose records were reviewed, 329 received at least 3 weeks of ganciclovir, with 62 (19%) receiving CMVIG. CMVIG was administered more frequently with CMV donor-positive/recipient-negative serostatus (p < 0.05). In multivariable models, patients who did not receive CMVIG as part of their prophylaxis were 3 times more likely to develop CMV infection (hazard ratio, 3.4; 95% confidence interval, 1.2-9.5) independent of CMV serostatus. However, CMVIG administration was not associated with decreased risk of episodes of CMV disease. Receipt of CMVIG was not associated with decreased risks of post-transplant morbidities (acute rejection, respiratory viral infection or early bronchiolitis obliterans) or morbidity within the first year after pediatric lung transplantation.
The use of CMVIG in addition to antiviral prophylaxis in pediatric lung transplantation requires further evaluation.
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