Monoclonal antibodies targeted against the immune checkpoint molecules CTLA-4 and PD-1 have recently obtained approval for the treatment of metastatic melanoma and advanced/refractory non small-cell ...lung cancers. Therefore, their use will not be limited anymore to selected hospitals involved in clinical trials. Indeed, they will be routinely prescribed in many cancer centers across the world. Besides their efficacy profile, these immune targeted agents also generate immune-related adverse events (irAEs). This new family of dysimmune toxicities remains largely unknown to the broad oncology community. Although severe irAEs remain rare (∼10% of cases under monotherapy), they can become life-threatening if not anticipated and managed appropriately. Over the last 5 years, Gustave Roussy has accumulated a significant experience in the prescription of immune checkpoint blockade (ICB) antibodies and the management of their toxicities. Together with the collaboration of Gustave Roussy's network of organ specialists with expertise in irAEs, we propose here some practical guidelines for the oncologist to help in the clinical care of patients under ICB immunotherapy.
Proteinuria is an important cause of progressive tubulo-interstitial damage. Whether proteinuria could trigger a renal lymphangiogenic response has not been established. Moreover, the temporal ...relationship between development of fibrosis, inflammation and lymphangiogenesis in chronic progressive kidney disease is not clear yet. Therefore, we evaluated the time course of lymph vessel (LV) formation in relation to proteinuria and interstitial damage in a rat model of chronic unilateral adriamycin nephrosis. Proteinuria and kidneys were evaluated up to 30 weeks after induction of nephrosis. LVs were identified by podoplanin/VEGFR3 double staining. After 6 weeks proteinuria was well-established, without influx of interstitial macrophages and myofibroblasts, collagen deposition, osteopontin expression (tubular activation) or LV formation. At 12 weeks, a ∼3-fold increase in cortical LV density was found (p<0.001), gradually increasing over time. This corresponded with a significant increase in tubular osteopontin expression (p<0.01) and interstitial myofibroblast numbers (p<0.05), whereas collagen deposition and macrophage numbers were not yet increased. VEGF-C was mostly expressed by tubular cells rather than interstitial cells. Cultured tubular cells stimulated with FCS showed a dose-dependent increase in mRNA and protein expression of VEGF-C which was not observed by human albumin stimulation. We conclude that chronic proteinuria provoked lymphangiogenesis in temporal conjunction with tubular osteopontin expression and influx of myofibroblasts, that preceded interstitial fibrosis.
The hormone calcitonin (CT) is primarily known for its pharmacologic action as an inhibitor of bone resorption, yet CT-deficient mice display increased bone formation. These findings raised the ...question about the underlying cellular and molecular mechanism of CT action. Here we show that either ubiquitous or osteoclast-specific inactivation of the murine CT receptor (CTR) causes increased bone formation. CT negatively regulates the osteoclast expression of Spns2 gene, which encodes a transporter for the signalling lipid sphingosine 1-phosphate (S1P). CTR-deficient mice show increased S1P levels, and their skeletal phenotype is normalized by deletion of the S1P receptor S1P3. Finally, pharmacologic treatment with the nonselective S1P receptor agonist FTY720 causes increased bone formation in wild-type, but not in S1P3-deficient mice. This study redefines the role of CT in skeletal biology, confirms that S1P acts as an osteoanabolic molecule in vivo and provides evidence for a pharmacologically exploitable crosstalk between osteoclasts and osteoblasts.
The diagnosis of pediatric-onset inflammatory bowel disease (PIBD) can be challenging in choosing the most informative diagnostic tests and correctly classifying PIBD into its different subtypes. ...Recent advances in our understanding of the natural history and phenotype of PIBD, increasing availability of serological and fecal biomarkers, and the emergence of novel endoscopic and imaging technologies taken together have made the previous Porto criteria for the diagnosis of PIBD obsolete.
We aimed to revise the original Porto criteria using an evidence-based approach and consensus process to yield specific practice recommendations for the diagnosis of PIBD. These revised criteria are based on the Paris classification of PIBD and the original Porto criteria while incorporating novel data, such as for serum and fecal biomarkers. A consensus of at least 80% of participants was achieved for all recommendations and the summary algorithm.
The revised criteria depart from existing criteria by defining 2 categories of ulcerative colitis (UC, typical and atypical); atypical phenotypes of UC should be treated as UC. A novel approach based on multiple criteria for diagnosing IBD-unclassified (IBD-U) is proposed. Specifically, these revised criteria recommend upper gastrointestinal endoscopy and ileocolonscopy for all suspected patients with PIBD, with small bowel imaging (unless typical UC after endoscopy and histology) by magnetic resonance enterography or wireless capsule endoscopy.
These revised Porto criteria for the diagnosis of PIBD have been developed to meet present challenges and developments in PIBD and provide up-to-date guidelines for the definition and diagnosis of the IBD spectrum.
Summary
Background
Risk benefit strategies in managing inflammatory bowel diseases (IBD) are dependent upon understanding the risks of uncontrolled inflammation vs those of treatments. Malignancy and ...mortality in IBD have been associated with disease‐related inflammation and immune suppression, but data are limited due to their rare occurrence.
Aim
To identify and describe the most common causes of mortality, types of cancer and previous or current therapy among children and young adults with paediatric‐onset IBD.
Methods
Information on paediatric‐onset IBD patients diagnosed with malignancy or mortality was prospectively collected via a survey in 25 countries over a 42‐month period. Patients were included if death or malignancy occurred after IBD diagnosis but before the age of 26 years.
Results
In total, 60 patients were identified including 43 malignancies and 26 fatal cases (9 due to cancer). Main causes of fatality were malignancies (n = 9), IBD or IBD‐therapy related nonmalignant causes (n = 10; including 5 infections), and suicides (n = 3). Three cases, all fatal, of hepatosplenic T‐cell lymphoma were identified, all were biologic‐naïve but thiopurine‐exposed. No other haematological malignancies were fatal. The 6 other fatal cancer cases included 3 colorectal adenocarcinomas and 3 cholangiocarcinomas (CCAs). Primary sclerosing cholangitis (PSC) was present in 5 (56%) fatal cancers (1 colorectal carcinoma, 3 CCAs and 1 hepatosplenic T‐cell lymphoma).
Conclusions
We report the largest number of paediatric‐onset IBD patients with cancer and/or fatal outcomes to date. Malignancies followed by infections were the major causes of mortality. We identified PSC as a significant risk factor for cancer‐associated mortality. Disease‐related adenocarcinomas were a commoner cause of death than lymphomas.
Total body fat percentage (%BF) evaluated by dual energy X-ray absorptiometry (DXA) scans (DXA %BF) is widely recognized as a precise measure of fatness. We aimed to establish national reference ...curves for DXA %BF, %BF calculated from skinfolds (SF %BF) and waist circumference (WC) in healthy children, and to compare agreement between the different methods.
Based on 11 481 physical examinations (anthropometry) and 1200 DXA scans from a longitudinal cohort of Danish children (n=2647), we established reference curves (LMS-method) for SF %BF, WC (birth to 14 years) and DXA %BF (8-14 years). Age- and sex-specific Z-scores for body mass index (BMI), WC and SF %BF were compared. Sensitivity and specificity were calculated for agreement of WC, SF %BF and BMI with DXA %BF to identify obese children (>+1 s.d.).
%BF differed with age, sex, pubertal stage and social class. SF %BF correlated strongly with DXA %BF (r=0.86). BMI and WC also correlated positively with DXA %BF (Z-scores; r= 0.78 and 0.69). Sensitivity and specificity were 79.5 and 93.8 for SF %BF, 75.9 and 90.3 for BMI and 59.2 and 95.4 for WC.
SF %BF showed the highest correlation and best agreement with DXA %BF in identifying children with excess fat (+1 s.d.).
To better understand molecular mechanisms regulating changes in metabolism, as observed e.g. in diabetes or neuronal disorders, the function of mitochondria needs to be precisely determined. The ...usual isolation methods such as differential centrifugation result in isolates of highly variable quality and quantity. To fulfill the need of a reproducible isolation method from solid tissues, which is suitable to handle parallel samples simultaneously, we developed a protocol based on anti-TOM22 (translocase of outer mitochondrial membrane 22 homolog) antibody-coupled magnetic beads. To measure oxygen consumption rate in isolated mitochondria from various mouse tissues, a traditional Clark electrode and the high-throughput XF Extracellular Flux Analyzer were used. Furthermore, Western blots, transmission electron microscopic and proteomic studies were performed to analyze the purity and integrity of the mitochondrial preparations. Mitochondrial fractions isolated from liver, brain and skeletal muscle by anti-TOM22 magnetic beads showed oxygen consumption capacities comparable to previously reported values and little contamination with other organelles. The purity and quality of isolated mitochondria using anti-TOM22 magnetic beads was compared to traditional differential centrifugation protocol in liver and the results indicated an obvious advantage of the magnetic beads method compared to the traditional differential centrifugation technique.
Lymphotoxin β-receptor (LTβR) signalling promotes lymphoid neogenesis and the development of tertiary lymphoid structures
, which are associated with severe chronic inflammatory diseases that span ...several organ systems
. How LTβR signalling drives chronic tissue damage particularly in the lung, the mechanism(s) that regulate this process, and whether LTβR blockade might be of therapeutic value have remained unclear. Here we demonstrate increased expression of LTβR ligands in adaptive and innate immune cells, enhanced non-canonical NF-κB signalling, and enriched LTβR target gene expression in lung epithelial cells from patients with smoking-associated chronic obstructive pulmonary disease (COPD) and from mice chronically exposed to cigarette smoke. Therapeutic inhibition of LTβR signalling in young and aged mice disrupted smoking-related inducible bronchus-associated lymphoid tissue, induced regeneration of lung tissue, and reverted airway fibrosis and systemic muscle wasting. Mechanistically, blockade of LTβR signalling dampened epithelial non-canonical activation of NF-κB, reduced TGFβ signalling in airways, and induced regeneration by preventing epithelial cell death and activating WNT/β-catenin signalling in alveolar epithelial progenitor cells. These findings suggest that inhibition of LTβR signalling represents a viable therapeutic option that combines prevention of tertiary lymphoid structures
and inhibition of apoptosis with tissue-regenerative strategies.
•Comparative study of different AOPs for micropollutants removal at full-scale•Oxidants photolysis is proven to be more efficient than UV-C in MPs removal.•Very low oxidant dosages (0.05–0.5mM) and ...contact time (4–18s) were applied•Average MPs removal of 55 and 48% was reached using H2O2 and PMS respectively.•H2O2/UV-C is more efficient than UV-C, in terms cost:efficiency (€/m3·order).
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The high chemical stability and the low biodegradability of a vast number of micropollutants (MPs) impede their correct treatment in urban wastewater treatment plants. In most cases, the chemical oxidation is the only way to abate them. Advanced Oxidation Processes (AOPs) have been experimentally proved as efficient in the removal of different micropollutants at lab-scale. However, there is not enough information about their application at full-scale. This manuscript reports the application of three different AOPs based on the addition of homogeneous oxidants hydrogen peroxide, peroxymonosulfate (PMS) and persulfate anions (PS), in the UV-C tertiary treatment of Estiviel wastewater treatment plant (Toledo, Spain) previously designed and installed in the facility for disinfection.
AOPs based on the photolytic decomposition of oxidants have been demonstrated as more efficient than UV-C radiation alone on the removal of 25 different MPs using low dosages (0.05–0.5 mM) and very low UV-C contact time (4–18 s). Photolysis of PMS and H2O2 reached similar average MPs removal in all the range of oxidant dosages, obtaining the highest efficiency with 0.5 mM and 18 s of contact time (48 and 55% respectively). Nevertheless, PMS/UV-C reached slightly higher removal than H2O2/UV-C at low dosages. So, these treatments are selective to degrade the target compounds, obtaining different removal efficiencies for each compound regarding the oxidizing agent, dosages and UV-C contact time.
In all the cases, H2O2/UV-C is more efficient than PMS/UV-C, comparing the ratio cost:efficiency (€/m3·order). Even H2O2/UV-C treatments are more efficient than UV-C alone. Thus, the addition of 0.5 mM of H2O2 compensates the increased of UV-C contact time and therefore the increase of electrical consumption, that it should be need to increase the removal of MPs by UV-C treatments alone.
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