Production of Biofuel via Hydrogenation of Lignin from Biomass

Historically, humans have been harnessing biomass as a source of energy since the time they knew to make a fire from woods. Even today, some countries still depend on woods as a main source of energy. Biologically, biomass contains carbon-, hydrogen- and oxygen-based matters that unify in a solid material and that are potentially to be converted to fuel. Lignin is one of the components present in lignocellulosic biomass and has been actively examined to be used for biofuel production. Issues arise with the chemical characteristic and rigidity of its structure, which a setback for its viability for biofuel conversion. However, such setbacks have been counteracted with the advances of lignin-based knowledge on its conversion to chemical precursors for biofuel conversion. Recently, investigations on hydrogenation as one of the chemical processes used can be potentially utilised for efficient and viable means for biofuel production

Neurodegeneration and Epilepsy in a Zebrafish Model of CLN3 Disease (Batten Disease)

The neuronal ceroid lipofuscinoses are a group of lysosomal storage disorders that comprise the most common, genetically heterogeneous, fatal neurodegenerative disorders of children. They are characterised by childhood onset, visual failure, epileptic seizures, psychomotor retardation and dementia. CLN3 disease, also known as Batten disease, is caused by autosomal recessive mutations in the CLN3 gene, 80–85% of which are a ~1 kb deletion. Currently no treatments exist, and after much suffering, the disease inevitably results in premature death. The aim of this study was to generate a zebrafish model of CLN3 disease using antisense morpholino injection, and characterise the pathological and functional consequences of Cln3 deficiency, thereby providing a tool for future drug discovery. The model was shown to faithfully recapitulate the pathological signs of CLN3 disease, including reduced survival, neuronal loss, retinopathy, axonopathy, loss of motor function, lysosomal storage of subunit c of mitochondrial ATP synthase, and epileptic seizures, albeit with an earlier onset and faster progression than the human disease. Our study provides proof of principle that the advantages of the zebrafish over other model systems can be utilised to further our understanding of the pathogenesis of CLN3 disease and accelerate drug discovery

Diagnosing Light Chain Amyloidosis on Temporal Artery Biopsies for Suspected Giant Cell Arteritis

Although still rarely diagnosed, amyloid light chain (AL) amyloidosis is the most common form of systemic amyloidosis. It is characterized by misfolded monoclonal immunoglobulin light chain fragments that accumulate extracellularly as amyloid fibrils, with consequent organ dysfunction. We report 2 such cases where initial symptoms and signs were identical to and mistaken for those of giant cell arteritis, associated with polymyalgia rheumatica. Neither patient responded to high-dose corticosteroids; instead, their temporal artery biopsies revealed amyloid deposits and other investigations confirmed a diagnosis of systemic AL amyloidosis. Review of the literature reveals similar cases of diagnostic confusion spanning 75 years. We have summarized the findings and learning points from cases reported in the past 30 years and highlight the need for increased awareness and investigation of this underrecognized syndrome

A 24-year experience of autologous stem cell transplantation for light chain amyloidosis patients in the United Kingdom

Autologous stem cell transplantation (ASCT) is considered to be the best method to achieve deep haematological/organ responses and improve survival in selected patients with AL amyloidosis. This field has been led by US centres and is less utilised in Europe. The introduction of effective chemotherapy agents for AL prompted us to re‐evaluate UK outcomes of ASCT in affected patients. A total of 264 AL amyloidosis patients treated with an ASCT between 1994 and 2018 were identified. Patient baseline characteristics, transplant‐related mortality (TRM) and overall survival (OS) were analysed. The median OS post‐ASCT was 87 months [95% confidence interval (CI): 77–106 months]. The median time from ASCT to next treatment was 48 months (95% CI: 29–55 months). A haematological response was achieved in 94·8% of patients and was a strong predictor of time to next treatment [P < 0·0001, hazard ratio (HR) = 1·75, 95% CI = 1·35–2·28] and OS (P = 0·007, HR = 1·91, 95% CI = 1·19–3·07). Organ response was: cardiac (n = 28, 60·9%), renal (n = 101, 76%) and liver (n = 7, 13·5%). Overall TRM was 8·7%, with a significant reduction over time (1994–2000: 18·8%; 2001–2006: 13·6%; 2007–2012: 6·2%; 2013–2018: 1·1%). In conclusion, ASCT is significantly safer and remains a highly effective treatment with excellent long‐term survival; it should be more widely considered as a treatment option for systemic AL amyloidosis

Impact of early response on outcomes in AL amyloidosis following treatment with frontline Bortezomib

The outcomes in systemic AL amyloidosis are dependent on the depth of haematologic response. However, there is limited data on the impact of the speed of response on outcomes. Here we report the impact of speed of response in a cohort of AL patients treated with upfront Bortezomib. Patients seen from February 2010 until August 2019 are included in the present analysis. 1194 & 1133 patients comprised the ITT and 1-month landmark cohorts. In the landmark cohort, 137 (11.5%), 270 (22.6%), 252 (21.1%) and 352 (31.1%) patients had a CR, VGPR, PR and NR at 1-month. Patients with ≥ VGPR at 1-month had significantly better survival (median not reached; at the end of 1, 2, 5,10 years, 87%/92%, 83%/87%, 68%/72% and 63%/58% of patients in CR/VGPR, respectively, were alive) compared to those with a PR (median OS 60 months) or NR (median OS 32 months) (p  20 mg/l (p = 0.005). Reaching ≥ VGPR at 1-month significantly improved survival in all Mayo disease stages. In conclusion, patients achieving an early deep haematologic response have a significantly superior survival irrespective of cardiac involvement

Haematologic responses and survival do not significantly decrease with subsequent lines of therapy in systemic immunoglobulin light chain amyloidosis: results from an analysis of real-world longitudinal data

Systemic immunoglobulin light chain amyloidosis (AL) is an incurable disorder, and the natural history is incompletely understood. In this study, we describe its natural history based on an analysis of real-world longitudinal data. All patients seen at the National Amyloidosis Centre, UK, between February 2010 and August 2019 and treated with up-front bortezomib are included. In all, 1 276 patients received the first-line treatment; 259, 85, and 32 patients received second, third, and fourth treatment lines, respectively. Among patients requiring further treatment after the first line, 77·2% started the second line within two years of the first line; 50·5%, 50·6%, 40·1% and 40·6% of patients had achieved at least very good partial response after the first, second, third and fourth treatment lines. Median overall survival (OS) from first, second, third and fourth lines was 45 months, 56 months, 37 months and not reached, respectively (P = 0·109). In summary, although relapses occur in AL amyloidosis, the outcomes and responses do not worsen with each subsequent relapse, making it attractive to design therapeutics with curative intent

Mitral Valve Coaptation Reserve Index:A Model to Localize Individual Resistance to Mitral Regurgitation Caused by Annular Dilation

Objectives: The objective of this study was to develop a mathematical model for mitral annular dilatation simulation and determine its effects on the individualized mitral valve (MV) coaptation reserve index (CRI). Design: A retrospective analysis of intraoperative transesophageal 3-dimensionalechocardiographic MV datasets was performed. A mathematical model was created to assess the mitral CRI for each leaflet segment (A1-P1, A2-P2, A3-P3). Mitral CRI was defined as the ratio between the coaptation reserve (measured coaptation length along the closure line) and an individualized correction factor. Indexing was chosen to correct for MV sphericity and area of largest valve opening. Mathematical models were created to simulate progressive mitral annular dilatation and to predict the effect on the individual mitral CRI. Setting: At a single-center academic hospital. Participants: Twenty-five patients with normally functioning MVs undergoing cardiac surgery. Interventions: None. Measurements and Main Results: Direct measurement of leaflet coaptation along the closure line showed the lowest amount of coaptation (reserve) near the commissures (A1-P1 0.21 ± 0.05 cm and A3-P3 0.22 ± 0.06 cm), and the highest amount of coaptation (reserve) at region A2 to P2 0.25 ± 0.06 cm. After indexing, the A2-to-P2 region was the area with the lowest CRI in the majority of patients, and also the area with the least resistance to mitral regurgitation (MR) occurrence after simulation of progressive annular dilation. Conclusions: Quantification and indexing of mitral coaptation reserve along the closure line are feasible. Indexing and mathematical simulation of progressive annular dilatation consistently showed that indexed coaptation reserve was lowest in the A2-to-P2 region. These results may explain why this area is prone to lose coaptation and is often affected in MR

Diagnosis, pathogenesis and outcome in leucocyte chemotactic factor 2 (ALECT2) amyloidosis

Introduction: Renal biopsy series from North America suggest that leucocyte chemotactic factor 2 (ALECT2) amyloid is the third most common type of renal amyloid. We report the first case series from a European Centre of prevalence, clinical presentation and diagnostic findings in ALECT2 amyloidosis and report long-term patient and renal outcomes for the first time. Methods: We studied the clinical features, diagnostic investigations and the outcome of all patients with ALECT2 amyloidosis followed systematically at the UK National Amyloidosis Centre (NAC) between 1994 and 2015. Results: Twenty-four patients, all non-Caucasian, were diagnosed with ALECT2 amyloidosis representing 1.3% of all patients referred to the NAC with biopsy-proved renal amyloid. Diagnosis was made at median age of 62 years, usually from renal histology; immunohistochemical staining was definitive for ALECT2 fibril type. Median estimated glomerular filtration rate (GFR) at diagnosis was 33 mL/min/1.73 m2 and median proteinuria was 0.5 g/24 h. Hepatic amyloid was evident on serum amyloid P component (SAP) scintigraphy in 11/24 cases but was not associated with significant derangement of liver function. No patient had evidence of cardiac amyloidosis or amyloid neuropathy. Median follow-up was 4.8 (range 0.5–15.2) years, during which four patients died and four progressed to end-stage renal disease. The mean rate of GFR loss was 4.2 (range 0.5–9.6) mL/min/year and median estimated renal survival from diagnosis was 8.2 years. Serial SAP scans revealed little or no change in total body amyloid burden. Conclusions: ALECT2 amyloidosis is a relatively benign type of renal amyloid, associated with a slow GFR decline, which is reliably diagnosed on renal histology. Neither the molecular basis nor the factors underlying the apparent restriction of ALECT2 amyloidosis to non-Caucasian populations have been determined

Autologous stem cell transplantation vs bortezomib based chemotheraphy for the first‐line treatment of systemic light chain amyloidosis in the UK

OBJECTIVES: The benefit of autologous stem cell transplantation (ASCT) in the treatment of light chain (AL) amyloidosis requires re-evaluation in the modern era. This retrospective case-matched study compares ASCT to bortezomib for the treatment of patients with AL amyloidosis. METHODS: Newly diagnosed patients with AL amyloidosis treated with ASCT or bortezomib between 2001-2018 were identified. Patients were excluded if the time from diagnosis to treatment exceeded 12 months. Patients were matched on a 1:1 basis, using a propensity matched scoring approach. RESULTS: A total of 136 propensity-score matched patients were included (ASCT n= 68, bortezomib n=68). There was no significant difference in overall survival at two years (p=0.908, HR: 0.95, CI:0.41-2.20). For ASCT vs. bortezomib: overall haematological response rate at six months was 90.6% vs. 92.5%; organ response at 12 months: cardiac (70.0% vs. 54%, p>0.999), renal (74% vs.24%, p=0.463)) liver (21% vs. 22%, p=0.048); median progression free survival (50 vs. 42 months p=0.058, HR:0.61, CI:0.37-1.02) and time to next treatment (68 vs. 45 months, p=0.145, HR:0.61, CI:0.31-1.19). More patients required treatment in the bortezomib group compared to ASCT group at 24 months (41 vs. 23, Chi squared p=0.004) and 48 months (57 vs 41, Chi squared p= 0.004). CONCLUSIONS: This small retrospective study suggests that there is no clear survival advantage of ASCT over bortezomib therapy. A prospective randomised controlled trial evaluating ASCT in AL amyloidosis is critically needed