The lung in amyloidosis

Amyloidosis is a disorder caused by misfolding of autologous protein and its extracellular deposition as fibrils, resulting in vital organ dysfunction and eventually death. Pulmonary amyloidosis may be localised or part of systemic amyloidosis.Pulmonary interstitial amyloidosis is symptomatic only if the amyloid deposits severely affect gas exchange alveolar structure, thus resulting in serious respiratory impairment. Localised parenchymal involvement may be present as nodular amyloidosis or as amyloid deposits associated with localised lymphomas. Finally, tracheobronchial amyloidosis, which is usually not associated with evident clonal proliferation, may result in airway stenosis.Because the treatment options for amyloidosis are dependent on the fibril protein type, the workup of all new cases should include accurate determination of the amyloid protein. Most cases are asymptomatic and need only a careful follow-up. Diffuse alveolar-septal amyloidosis is treated according to the underlying systemic amyloidosis. Nodular pulmonary amyloidosis is usually localised, conservative excision is usually curative and the long-term prognosis is excellent. Tracheobronchial amyloidosis is usually treated with bronchoscopic interventions or external beam radiation therapy

Energy Densities of Brown Trout (Salmo trutta) and Its Main Prey Items in an Alpine Stream of the Slizza Basin (Northwest Italy)

ABSTRACT In the present study, energy densities of 80 adult brown trout (Salmo trutta), seasonally sampled in an alpine stream in the eastern Alps and energy densities of their main prey items, were determined. The energy density (J/g wet mass) and dry weight content (%) of fish were highly correlated (p<0.00 1) and averaged 5, 611.6 ± 857.9 J/g wet mass and 25.3 ± 2.1% dry weight, respectively. Energy density values were significantly higher in fish sampled in spring than in other seasons. No major changes in the energy content were observed due to age or sex. Macroinvertebrates. particularly Ephemeroptera and Diptera, were the major food source of brown trout in the sampled area. Their gross energy content varied within a wide range of values (1, 654–5, 110 J/g wet weight), depending on the taxa and family or genus within a given taxon

Metabolic rate and climate change across latitudes: Evidence of mass-dependent responses in aquatic amphipods

Predictions of individual responses to climate change are often based on the assumption that temperature affects individuals’ metabolism independently of their body mass. However, empirical evidence indicates that interactive effects exist. Here, we investigated the response of individual Standard Metabolic Rate (SMR) to annual temperature range and forecasted temperature rises of 0.6-1.2°C above the current maxima, under the conservative climate change scenario IPCC-RCP2.6. As a model organism we used the amphipod Gammarus insensibilis, collected across latitudes along the western coast of the Adriatic Sea down to the southernmost limit of the species’ distributional range, with individuals varying in body mass (0.4-13.57mg). Overall, we found that the effect of temperature on SMR is mass-dependent. Within the annual temperature range, the mass-specific SMR of small/young individuals increased with temperature at a greater rate (activation energy: E=0.48 eV) than large/old ones (E=0.29 eV), with a higher metabolic level for high-latitude than low-latitude populations. However, under the forecasted climate conditions, the large individuals’ mass-specific SMR responded differently across latitudes. Unlike the higher-latitude population, whose mass-specific SMR increased in response to the forecasted climate change across all size classes, in the lower-latitude populations, this increase was not seen in large individuals. The larger/older conspecifics at lower latitudes could therefore be the first to experience the negative impacts of warming on metabolism-related processes. Although the ecological collapse of such a basic trophic level (aquatic amphipods) due to climate change would have profound consequences for population ecology, the risk is significantly mitigated by phenotypic and genotypic adaptation

Lenalidomide and dexamethasone in relapsed/refractory immunoglobulin light chain (AL) amyloidosis: results from a large cohort of patients with long follow-up.

SummaryLenalidomide and dexamethasone (RD) is a standard treatment in relapsed/refractory immunoglobulin light chain (AL) amyloidosis (RRAL). We retrospectively investigated toxicity, efficacy and prognostic markers in 260 patients with RRAL. Patients received a median of two prior treatment lines (68% had been bortezomib‐refractory; 33% had received high‐dose melphalan). The median treatment duration was four cycles. The 3‐month haematological response rate was 31% [very good haematological response (VGHR) in 18%]. The median follow‐up was 56·5 months and the median overall survival (OS) and haematological event‐free survival (haemEFS) were 32 and 9 months. The 2‐year dialysis rate was 15%. VGHR resulted in better OS (62 vs. 26 months, P < 0·001). Cardiac progression predicted worse survival (22 vs. 40 months, P = 0·027), although N‐terminal prohormone of brain natriuretic peptide (NT‐proBNP) increase was frequently observed. Multivariable analysis identified these prognostic factors: NT‐proBNP for OS [hazard ratio (HR) 1·71; P < 0·001]; gain 1q21 for haemEFS (HR 1·68, P = 0·014), with a trend for OS (HR 1·47, P = 0·084); difference between involved and uninvolved free light chains (dFLC) and light chain isotype for OS (HR 2·22, P < 0·001; HR 1·62, P = 0·016) and haemEFS (HR 1·88, P < 0·001; HR 1·59, P = 0·008). Estimated glomerular filtration rate (HR 0·71, P = 0·004) and 24‐h proteinuria (HR 1·10, P = 0·004) were prognostic for renal survival. In conclusion, clonal and organ biomarkers at baseline identify patients with favourable outcome, while VGHR and cardiac progression define prognosis during RD treatment

Quantum bath engineering of a high impedance microwave mode through quasiparticle tunneling

We demonstrate a new approach to dissipation engineering in microwave quantum optics. For a single mode, dissipation usually corresponds to quantum jumps, where photons are lost one by one. Here, we are able to tune the minimal number of lost photons per jump to be two (or more) with a simple dc voltage. As a consequence, different quantum states experience different dissipation. Causality implies that the states must also experience different energy shifts. Our measurements of these Lamb shifts are in good agreement with the predictions of the Kramers-Kronig relations for single quantum states in a regime of highly non-linear bath coupling. This work opens new possibilities for quantum state manipulation in circuit QED, without relying on the Josephson effect

Axion-Like Particles, Cosmic Magnetic Fields and Gamma-Ray Astrophysics

Axion-Like Particles (ALPs) are predicted by many extensions of the Standard Model and give rise to characteristic dimming and polarization effects in a light beam travelling in a magnetic field. In this Letter, we demonstrate that photon-ALP mixing in cosmic magnetic fields produces an observable distortion in the energy spectra of distant gamma-ray sources (like AGN) for ranges of the ALP parameters allowed by all available constraints. The resulting effect is expected to show up in the energy band 100 MeV - 100 GeV, and so it can be serched with the upcoming GLAST mission.Comment: 17 pages, 6 figures; accepted for publication in Physics Letters B. Revised versio

Prospective urinary albumin/creatinine ratio for diagnosis, staging, and organ response assessment in renal AL amyloidosis: results from a large cohort of patients

Abstract Objectives Quantification of 24 h-proteinuria is the gold standard for diagnosing, staging, and monitoring of patients with renal AL amyloidosis. However, 24 h-urine collection is cumbersome and may result in preanalytical error. In this prospective study, we investigated the role of urinary albumin/creatinine ratio (UACR) (cut-off: 300 mg/g) identifying renal involvement, evaluated a UACR-based staging system (UACR cut-off: 3,600 mg/g) and assessed whether UACR response (UACR decrease >30% without worsening in eGFR >25%) predicts renal outcome in 531 patients with newly-diagnosed AL amyloidosis. Methods From October 2013 paired 24 h-proteinuria and UACR (on first morning void) were measured in all newly-diagnosed patients with AL amyloidosis. Correlation between 24 h-proteinuria and UACR at baseline was assessed by Pearson's r test. Impact of UACR response on renal outcome was assessed in randomly created testing (n=354) and validation (n=177) cohorts. Results A strong linear correlation was found between 24 h-proteinuria and UACR at baseline (r=0.90; p<0.001). After a median follow-up of 31 months, 57 (11%) patients required dialysis. A UACR-based renal staging system identified three stages with significantly higher dialysis rate at 36 months comparing stage I with stage II and stage II with stage III. Achieving a renal response, according to a UACR-based criterion, resulted in lower dialysis rate in both testing and validation cohorts. Conclusions UACR is a reliable marker for diagnosis, prognosis, and organ response assessment in renal AL amyloidosis and can reliably replace 24 h-proteinuria in clinical trials and individual patients' management

Minimal residual disease negativity by next-generation flow cytometry is associated with improved organ response in AL amyloidosis

© The Author(s) 2021.Light chain (AL) amyloidosis is caused by a small B-cell clone producing light chains that form amyloid deposits and cause organ dysfunction. Chemotherapy aims at suppressing the production of the toxic light chain (LC) and restore organ function. However, even complete hematologic response (CR), defined as negative serum and urine immunofixation and normalized free LC ratio, does not always translate into organ response. Next-generation flow (NGF) cytometry is used to detect minimal residual disease (MRD) in multiple myeloma. We evaluated MRD by NGF in 92 AL amyloidosis patients in CR. Fifty-four percent had persistent MRD (median 0.03% abnormal plasma cells). There were no differences in baseline clinical variables in patients with or without detectable MRD. Undetectable MRD was associated with higher rates of renal (90% vs 62%, p = 0.006) and cardiac response (95% vs 75%, p = 0.023). Hematologic progression was more frequent in MRD positive (0 vs 25% at 1 year, p = 0.001). Altogether, NGF can detect MRD in approximately half the AL amyloidosis patients in CR, and persistent MRD can explain persistent organ dysfunction. Thus, this study supports testing MRD in CR patients, especially if not accompanied by organ response. In case MRD persists, further treatment could be considered, carefully balancing residual organ damage, patient frailty, and possible toxicity.This study was supported by a grant from CARIPLO “Molecular mechanisms of Ig toxicity in age-related plasma cell dyscrasias no. 2015-0591”, by a grant from the Black Swan Research Initiative from the International Myeloma Foundation “Automated multidimensional flow cytometry for high-sensitive screening and to monitor response in AL amyloidosis”, by a grant from CARIPLO “Structure–function relation of amyloid: understanding the molecular bases of protein misfolding diseases to design new treatments no. 2013-0964”, by a grant from the Amyloidosis Foundation “Investigating new therapies to treat AL amyloidosis”, and by a grant from Cancer Research UK, FCAECC and AIRC under the Accelerator Award 2017 Program “Early detection and intervention: understanding the mechanisms of transformation and hidden resistance of incurable hematological malignancies”, by a grant from CARIPLO “Harnessing the plasma cell secretory capacity against systemic light chain amyloidosis” (no. 2018-0257), by a grant from the Italian Ministry of Health “Towards effective, patient-tailored anti-plasma cell therapies in AL amyloidosis: predicting drug response and overcoming drug resistance” (GR-2018-12368387). This study has also supported the Centro de Investigación Biomédica en Red—Área de Oncología—del Instituto de Salud Carlos III (CIBERONC; CB16/12/00369, CB16/12/00400, and CB16/12/00489) and the Instituto de Salud Carlos III/Subdirección General de Investigación Sanitaria (FIS No. PI13/02196). G.P. is supported in part by the Bart Barlogie Young Investigator Award from the International Myeloma Society (IMS). P.M. is supported in part by a fellowship grant form Collegio Ghislieri (Pavia). We acknowledge the study coordinator and data manager Anna Carnevale Baraglia