Softwood is an abundantly available feedstock for the bio-based industry. However, achieving cost-effective sugar release is particularly challenging, owing to its guaiacyl-only lignin. Here, we ...report the highly effective pretreatment of the softwood pine (
Pinus sylvestris
) using ionoSolv pretreatment, a novel ionic liquid-based lignocellulose fractionation technology. Three protic, low-cost ionic liquids, 1-butylimidazolium hydrogen sulfate, triethylammonium hydrogen sulfate and
N
,
N
-dimethylbutylammonium hydrogen sulfate, were used to fractionate the biomass into a carbohydrate-rich pulp and a lignin. The carbohydrate-rich pulp was hydrolysed into fermentable sugars by enzymatic saccharification. Under the most successful pretreatment conditions, quantitative glucose release from the pulp was achieved, which equates to a projected glucose release of 464 mg per gram of pine wood entering the process. We further intensified the process by increasing the solid to solvent ratio up to 1 : 2 g g
−1
while maintaining saccharification yields of 75% of the theoretical maximum. We also demonstrate for the first time that
N
,
N
-dimethylbutylammonium hydrogen sulfate, DMBAHSO
4
, is an excellent low-cost pretreatment solvent, surpassing the pretreatment effectiveness of its symmetrically substituted analogue triethylammonium hydrogen sulfate. This shows that ionoSolv pretreatment with protic hydrogen sulfate ionic liquids is a truly feedstock-independent pretreatment option, further increasing the commercial potential of this pretreatment technology.
Softwood is an abundantly available feedstock for the bio-based industry, however, achieving cost-effective sugar release is particularly challenging owing to its guaiacyl-only lignin.
Cost-effective fractionation (pretreatment) of lignocellulosic biomass is necessary to enable its large-scale use as a source of liquid fuels, bio-based materials and bio-derived chemicals. While a ...number of ionic liquids (ILs) have proven capable of highly effective pretreatment, their high cost presents a barrier to commercial viability. In this study, we investigate in detail the application of the low-cost (ca. $1 kg-1) ionic liquid triethylammonium hydrogen sulfate for the fractionation of the grass Miscanthus x giganteus into a cellulose rich pulp, a lignin and a distillate. We found that up to 85% of the lignin and up to 100% of the hemicellulose were solubilized into the IL solution. The hemicellulose dissolved mainly in monomeric form, and pentoses were partially converted into furfural. Up to 77% of the glucose contained in the biomass could be released by enzymatic saccharification of the pulp. The IL was successfully recovered and reused four times. A 99% IL recovery was achieved each time. Effective lignin removal and high saccharification yields were maintained during recycling, representing the first demonstration that repeated IL use is feasible due to the self-cleaning properties of the non-distillable solvent. We further demonstrate that furfural and acetic acid can be separated quantitatively from the non-volatile IL by simple distillation, providing an easily recoverable, valuable co-product stream, while IL degradation products were not detected. We further include detailed mass balances for glucose, hemicellulose and lignin, and a preliminary techno-economic estimate for the fractionation process. This is the first demonstration of an efficient and repeated lignocellulose fractionation with a truly low-cost IL, and opens a path to an economically viable IL-based pretreatment process.
In the present study, we used a low-cost protic ionic liquid, 1-methylimidazolium chloride, to simultaneously fractionate heavy metal contaminated wood and extract the metals from the wood at ...elevated temperature and short reaction time. This treatment selectively dissolves the lignin and hemicellulose in the biomass, leaving a solid cellulose-rich pulp, while coordinating and extracting 80-100% of the metal species present in the wood in a one-pot process. The lignin stream was recovered from the liquor and the cellulose was hydrolysed and then fermented into ethanol. The ionic liquid was recycled 6 times and the metals were recovered from the liquor
via
electrodeposition. This is the first time that highly contaminated waste wood has been integrated into a process which does not produce a contaminated waste stream, but instead valorises the wood as a feedstock for renewable chemicals, materials and fuels, while efficiently recovering the metals, converting a toxic environmental hazard into a rich source of biorenewables. We have therefore used an otherwise problematic waste as a low-cost lignocellulsoic feedstock for a circular bioeconomy concept.
In the present study, we used a low-cost protic ionic liquid, 1-methylimidazolium chloride, to simultaneously fractionate heavy metal contaminated wood and extract the metals from the wood at elevated temperature and short reaction time.
Amongst therapeutic radiopharmaceuticals, targeted alpha therapy (TαT) can deliver potent and local radiation selectively to cancer cells as well as the tumor microenvironment and thereby control ...cancer while minimizing toxicity. In this review, we discuss the history, progress, and future potential of TαT in the treatment of prostate cancer, including dosimetry-individualized treatment planning, combinations with small-molecule therapies, and conjugation to molecules directed against antigens expressed by prostate cancer cells, such as prostate-specific membrane antigen (PSMA) or components of the tumor microenvironment. A clinical proof of concept that TαT is efficacious in treating bone-metastatic castration-resistant prostate cancer has been demonstrated by radium-223 via improved overall survival and long-term safety/tolerability in the phase III ALSYMPCA trial. Dosimetry calculation and pharmacokinetic measurements of TαT provide the potential for optimization and individualized treatment planning for a precision medicine-based cancer management paradigm. The ability to combine TαTs with other agents, including chemotherapy, androgen receptor-targeting agents, DNA repair inhibitors, and immuno-oncology agents, is under investigation. Currently, TαTs that specifically target prostate cancer cells expressing PSMA represents a promising therapeutic approach. Both PSMA-targeted actinium-225 and thorium-227 conjugates are under investigation. The described clinical benefit, safety and tolerability of radium-223 and the recent progress in TαT trial development suggest that TαT occupies an important new role in prostate cancer treatment. Ongoing studies with newer dosimetry methods, PSMA targeting, and novel approaches to combination therapies should expand the utility of TαT in prostate cancer treatment.
Background:CD147 (basigin, EMMPRIN) is a multifunctional, highly conserved glycoprotein enriched in pancreatic ductal adenocarcinomas (PDACs) which is associated with poor prognosis in many ...malignancies. The role of CD147 in pancreatic cancer, however, remains elusive.Methods and Results:Silencing of CD147 by RNA interference (RNAi) reduced the proliferation rate of MiaPaCa2 and Panc1 cells. CD147 is required for the function and expression of the monocarboxylate transporters MCT1 and MCT4 that are expressed in human PDAC cells as demonstrated by real-time reverse transcription-PCR (RT-PCR) as well as immunohistology. MCT1 and MCT4 are the natural transporters of lactate, and MiaPaCa2 cells exhibited a high rate of lactate production, which is characteristic for the Warburg effect, an early hallmark of cancer that confers a significant growth advantage. Further induction of lactate production by sodium azide in MiaPaCa2 cells increased MCT1 as well as MCT4 expression. CD147 silencing inhibited the expression and function of MCT1 and MCT4 and resulted in an increased intracellular lactate concentration. Addition of exogenous lactate inhibited cancer cell growth in a dose-dependent fashion. In vivo, knock-down of CD147 in MiaPaCa2 cells by inducible short hairpin RNA (shRNA)-mediated CD147 silencing reduced invasiveness through the chorioallantoic membrane of chick embryos (CAM assay) and inhibited tumourigenicity in a xenograft model in nude mice.Conclusion: The function of CD147 as an ancillary protein that is required to sustain the expression and function of MCT1 and MCT4 is involved in the association of CD147 expression with the malignant potential of pancreatic cancer cells exhibiting the Warburg effect.
Surgery is gold-standard for correction of Peyronie's curvature. Grafting is preferred in advanced deviations. We present our novel surgical technique and early results of grafting with collagen ...fleece. Patients with stable Peyronie's disease (PD) were included. Grafting was performed by a ready-to-use collagen fleece coated with tissue sealant (TachoSil, Nycomed, Konstanz, Germany), following partial plaque excision/incision. Results of correction were documented by artificial erection. In all, n=70 consecutive patients underwent surgery. Mean patient age was 56.4 years (range: 33-72); 88.6% of patients had dorsal deviation, 11.4% lateral or ventral deviation. Grafting after partial plaque excision was performed in 61 patients (87.1%), after plaque incision in 2 (2.9%) patients. In the former patients, mean operative time was 94.2 min (range: 65-165). Totally straightness was achieved in 83.6%. Three patients required surgical drainage because of subcutaneous haematoma formation. After mean early follow-up of 5.2 days (range: 2-15), glans sensation was normal in 56 patients (91.8%). Seven patients (10.0%) underwent Nesbit procedure alone. Grafting by collagen fleece in PD is feasible and promising. Major advantages are decreased operative times and easy application. Moreover, an additional haemostatic effect is provided. However, long-term clinical outcomes are necessary to confirm these encouraging findings.
We report on the pretreatment of poplar wood with three different 1-ethyl-3-methylimidazolium ionic liquids, EMimOAc, EMimMeSO
, and EMimHSO
, at varying water contents from 0-40 wt% at 100 °C. The ...performance was evaluated by observing the lignin and hemicellulose removal, as well as enzymatic saccharification and lignin yield. The mechanism of pretreatment varied between the ionic liquids studied, with the hydrogen sulfate ionic liquid performing delignification and hemicellulose hydrolysis more effectively than the other solvents across the investigated water content range. The acetate ionic liquid produced superior glucose yield at low water contents, while the hydrogen sulfate ionic liquid performed better at higher water contents and produced a recoverable lignin. The methanesulfonate ionic liquid did not introduce significant fractionation or enhancement of saccharification yield under the conditions used. These findings help distinguish the roles of anion hydrogen bonding, solvent acidity, and water content on ionic liquid pretreatment and can aid with anion and water content selections for different applications.
We evaluated angiogenesis-targeted sunitinib therapy in a randomized, double-blind trial of metastatic castration-resistant prostate cancer (mCRPC).
Men with progressive mCRPC after docetaxel-based ...chemotherapy were randomly assigned 2:1 to receive sunitinib 37.5 mg/d continuously or placebo. Patients also received oral prednisone 5 mg twice daily. The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS). Two interim analyses were planned.
Overall, 873 patients were randomly assigned to receive sunitinib (n = 584) or placebo (n = 289). The independent data monitoring committee stopped the study for futility after the second interim analysis. After a median overall follow-up of 8.7 months, median OS was 13.1 months and 11.8 months for sunitinib and placebo, respectively (hazard ratio HR, 0.914; 95% CI, 0.762 to 1.097; stratified log-rank test, P = .168). PFS was significantly improved in the sunitinib arm (median 5.6 v 4.1 months; HR, 0.725; 95% CI, 0.591 to 0.890; stratified log-rank test, P < .001). Toxicity and rates of discontinuations because of adverse events (AEs; 27% v 7%) were greater with sunitinib than placebo. The most common treatment-related grade 3/4 AEs were fatigue (9% v 1%), asthenia (8% v 2%), and hand-foot syndrome (7% v 0%). Frequent treatment-emergent grade 3/4 hematologic abnormalities were lymphopenia (20% v 11%), anemia (9% v 8%), and neutropenia (6% v < 1%).
The addition of sunitinib to prednisone did not improve OS compared with placebo in docetaxel-refractory mCRPC. The role of antiangiogenic therapy in mCRPC remains investigational.
Background
Intratumoural lymphocytic infiltration is strongly associated with the outcome of many human epithelial cancers. The current paper investigated whether subpopulations of ...tumour-infiltrating T lymphocytes are associated with certain clinicopathological parameters and the prognosis of patients with invasive bladder cancer (BCa).
Patients and methods
The infiltration densities of the adaptive immune markers CD3 (the whole T cell population), FOXP3 (regulatory T cells; Tregs), CD8 (T effector cells) and CD45R0 (T effector memory cells) were analysed by immunohistochemistry and image analysis with tissue microarrays of tumour tissues from 149 patients with invasive BCa treated with radical cystectomy. The findings were correlated with certain clinicopathological parameters.
Results
Higher FOXP3/CD3 OS:
p
= 0.016, HR 1.29, 95 % confidence intervals (95 % CIs 1.05–1.59) and FOXP3/CD8 (OS:
p
= 0.013, HR 1.32, 95 % CIs 1.06–1.65) ratios were significantly associated with briefer overall survival and time to cancer-specific death; the latter ratio represented an independent prognostic factor according to a multivariate analysis adjusted for pathological T and N stages (HR 1.32, 95 % CIs 1.05–1.67,
p
= 0.018). The infiltration densities of individual markers (CD3, CD8, FOXP3 and CD45R0) were not significantly associated with clinicopathological parameters or survival; however, a trend towards a better outcome was observed for higher log-transformed CD8 (
p
= 0.070, HR 0.80, 95 % CIs 0.63–1.02) and CD3 (
p
= 0.113, HR 0.84, 95 % CIs 0.68–1.04) infiltration values.
Conclusions
A high fraction of Tregs amongst CD3- and CD8-positive lymphocytes indicated a poor prognosis, thereby emphasising the important role that Tregs play in the suppression of the anti-tumour immune response. No single lymphocytic marker was significantly correlated with clinical outcomes, but high CD3 and CD8 infiltration showed trends towards better prognosis.
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