Weight loss, hyperglycaemia and diabetes are known features of pancreatic cancer. We quantified the timing and the amount of changes in body mass index (BMI) and glycated haemoglobin (HbA1c), and ...their association with pancreatic cancer from five years before diagnosis.
A matched case-control study was undertaken within 590 primary care practices in England, United Kingdom. 8,777 patients diagnosed with pancreatic cancer (cases) between 1st January 2007 and 31st August 2020 were matched to 34,979 controls by age, gender and diabetes. Longitudinal trends in BMI and HbA1c were visualised. Odds ratios adjusted for demographic and lifestyle factors (aOR) and 95% confidence intervals (CI) were calculated with conditional logistic regression. Subgroup analyses were undertaken according to the diabetes status.
Changes in BMI and HbA1c observed for cases on longitudinal plots started one and two years (respectively) before diagnosis. In the year before diagnosis, a 1 kg/m2 decrease in BMI between cases and controls was associated with aOR for pancreatic cancer of 1.05 (95% CI 1.05 to 1.06), and a 1 mmol/mol increase in HbA1c was associated with aOR of 1.06 (1.06 to 1.07). ORs remained statistically significant (p < 0.001) for 2 years before pancreatic cancer diagnosis for BMI and 3 years for HbA1c. Subgroup analysis revealed that the decrease in BMI was associated with a higher pancreatic cancer risk for people with diabetes than for people without (aORs 1.08, 1.06 to 1.09 versus 1.04, 1.03 to 1.05), but the increase in HbA1c was associated with a higher risk for people without diabetes than for people with diabetes (aORs 1.09, 1.07 to 1.11 versus 1.04, 1.03 to 1.04).
The statistically significant changes in weight and glycaemic control started three years before pancreatic cancer diagnosis but varied according to the diabetes status. The information from this study could be used to detect pancreatic cancer earlier than is currently achieved. However, regular BMI and HbA1c measurements are required to facilitate future research and implementation in clinical practice.
The cytochrome P450 CYP168A1 from Pseudomonas aeruginosa was cloned and expressed in Escherichia coli followed by purification and characterization of function. CYP168A1 is a fatty acid hydroxylase ...that hydroxylates saturated fatty acids, including myristic (0.30 min-1), palmitic (1.61 min-1) and stearic acids (1.24 min-1), at both the ω-1- and ω-2-positions. However, CYP168A1 only hydroxylates unsaturated fatty acids, including palmitoleic (0.38 min-1), oleic (1.28 min-1) and linoleic acids (0.35 min-1), at the ω-1-position. CYP168A1 exhibited a catalytic preference for palmitic, oleic and stearic acids as substrates in keeping with the phosphatidylcholine-rich environment deep in the lung that is colonized by P. aeruginosa.
On the occurrence of cytochrome P450 in viruses Lamb, David C.; Follmer, Alec H.; Goldstone, Jared V. ...
Proceedings of the National Academy of Sciences - PNAS,
06/2019, Letnik:
116, Številka:
25
Journal Article
Recenzirano
Odprti dostop
Genes encoding cytochrome P450 (CYP; P450) enzymes occur widely in the Archaea, Bacteria, and Eukarya, where they play important roles in metabolism of endogenous regulatory molecules and exogenous ...chemicals. We now report that genes for multiple and unique P450s occur commonly in giant viruses in the Mimiviridae, Pandoraviridae, and other families in the proposed order Megavirales. P450 genes were also identified in a herpesvirus (Ranid herpesvirus 3) and a phage (Mycobacterium phage Adler). The Adler phage P450 was classified as CYP102L1, and the crystal structure of the open formwas solved at 2.5 Å. Genes encoding known redox partners for P450s (cytochrome P450 reductase, ferredoxin and ferredoxin reductase, and flavodoxin and flavodoxin reductase) were not found in any viral genome so far described, implying that host redox partners may drive viral P450 activities. Giant virus P450 proteins share no more than 25% identity with the P450 gene products we identified in Acanthamoeba castellanii, an amoeba host for many giant viruses. Thus, the origin of the unique P450 genes in giant viruses remains unknown. If giant virus P450 genes were acquired from a host, we suggest it could have been from an as yet unknown and possibly ancient host. These studies expand the horizon in the evolution and diversity of the enormously important P450 superfamily. Determining the origin and function of P450s in giant viruses may help to discern the origin of the giant viruses themselves.
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Mirena® is long-acting (5 years) contraceptive intrauterine device. It is composed of a hollow cylindrical drug reservoir (containing Levonorgestrel and polydimethylsiloxane), which ...is covered with a release rate controlling silicone membrane. This structure presents a manufacturing challenge and to date, there have been no literature reports on the manufacturing, product design and quality evaluation of these hollow cylindrical intrauterine devices. It is vital to develop a reproducible and robust manufacturing process for these long-acting intrauterine devices or systems to obtain an understanding the in vitro and in vivo performance of such drug-device combinations. In this study, a twin-syringe method with a customized mold was developed to manufacture hollow cylindrical polydimethylsiloxane (PDMS)-based levonorgestrel intrauterine systems (LNG-IUSs). Different mold materials, curing temperatures and times were screened to fabricate PDMS-drug reservoirs with good quality characteristics (easy demolding, good appearance and appropriate physicochemical characteristics). The prepared PDMS-drug reservoirs were covered with the release rate controlling membrane to fabricate the LNG-IUSs. Physicochemical characterization (drug content and content uniformity, powder X-Ray diffraction (PXRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and Fourier-transform infrared spectroscopy (FTIR) of the PDMS-drug reservoirs with different drug loadings (10%, 25% and 50% w/w) was conducted. Real-time in vitro drug release testing of LNG-IUSs with different drug loading was performed in normal saline (0.9% w/v NaCl) at 37 °C using a water bath shaker rotating at 100 rpm. The prepared PDMS-drug reservoirs demonstrated good and reproducible quality characteristics including appearance (smooth surfaces), targeted drug loading and good drug content uniformity in the PDMS matrix. The PXRD showed that the crystallinity of the API was maintained inside the PDMS matrix. DSC, TGA and FTIR confirmed the structure of the drug and the PDMS, indicating no interaction between the drug and the PDMS matrix in the prepared LNG-IUSs. Real-time in vitro drug release from the LNG-IUSs with different drug loadings showed zero-order release kinetics, and the drug release rate (based on daily release percentage) was inversely proportional to the drug loading.
Cabbage stem flea beetle (CSFB) is an important pest of oilseed rape that was controlled by neonicotinoid seed treatments until they were banned for this use in 2013. Since then, CSFB has been a ...difficult pest to control, partly due to widespread resistance to pyrethroid insecticides. Alternate solutions are necessary. Here, four entomopathogenic nematode (EPN) species were tested against CSFB adults under laboratory conditions. In addition, a bioassay was completed to test for EPN compatibility with a range of adjuvants (glycerin, xanthan gum and flame retardant) to protect EPNs from UV radiation and desiccation. Results show that EPNs have the potential to control CSFB adults under laboratory conditions.
caused 75% CSFB mortality at a concentration of 4000 nematodes/mL after six days,
caused 80% CSFB mortality when applied at a concentration of 40,000 nematodes/mL after two days,
caused 85% mortality at a concentration of 10,000 nematodes/mL after six days, and
caused no more than 70% CSFB mortality overall compared to the water control, which led to 23% mortality.
and
survival was 100% when exposed to adjuvants, except
with glycerin and
with flame retardant. Further research to evaluate the efficacy of EPN and adjuvants under field conditions is necessary.
The foreign body response to implantable biosensors has been successfully countered through the use of corticosteroids, such as dexamethasone. However, while controlling inflammation, dexamethasone ...also decreases angiogenesis, which may lead to delayed analyte readings. The concurrent application of VEGF with dexamethasone increases angiogenesis, but VEGF has physical stability issues and is not cost-effective. The use of l-DOPA, a small molecule drug shown to up-regulate VEGF in the Parkinsonian brain, can potentially resolve these issues by substituting for VEGF. In this work, l-DOPA was used for the first time as a pro-angiogenic agent to counteract dexamethasone-induced ischemia. Angiogenesis was modeled using the CAM assay and changes in blood vessel formation were recorded with both manual and digital techniques. As expected, dexamethasone reduced blood vessel formation in the CAM. Application of l-DOPA, on the other hand, increased blood vessel formation when dexamethasone and l-DOPA were administered simultaneously. This novel finding suggests the utility of l-DOPA in the field of implantable medical devices, such as biosensors, as well as tissue engineering applications where both a vascularized tissue environment and control of tissue response is desired.
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Recombinant
CYP51 (CaCYP51) proteins containing 23 single and 5 double amino acid substitutions found in clinical strains and the wild-type enzyme were expressed in
and purified by Ni
...-nitrilotriacetic acid agarose chromatography. Catalytic tolerance to azole antifungals was assessed by determination of the concentration causing 50% enzyme inhibition (IC
) using CYP51 reconstitution assays. The greatest increase in the IC
compared to that of the wild-type enzyme was observed with the five double substitutions Y132F+K143R (15.3-fold), Y132H+K143R (22.1-fold), Y132F+F145L (10.1-fold), G307S+G450E (13-fold), and D278N+G464S (3.3-fold). The single substitutions K143R, D278N, S279F, S405F, G448E, and G450E conferred at least 2-fold increases in the fluconazole IC
, and the Y132F, F145L, Y257H, Y447H, V456I, G464S, R467K, and I471T substitutions conferred increased residual CYP51 activity at high fluconazole concentrations.
testing of select CaCYP51 mutations in
showed that the Y132F, Y132H, K143R, F145L, S405F, G448E, G450E, G464S, Y132F+K143R, Y132F+F145L, and D278N+G464S substitutions conferred at least a 2-fold increase in the fluconazole MIC. The catalytic tolerance of the purified proteins to voriconazole, itraconazole, and posaconazole was far lower and limited to increased residual activities at high triazole concentrations for certain mutations rather than large increases in IC
values. Itraconazole was the most effective at inhibiting CaCYP51. However, when tested against CaCYP51 mutant strains, posaconazole seemed to be the most resistant to changes in MIC as a result of CYP51 mutation compared to itraconazole, voriconazole, or fluconazole.
Abstract
Lactic acid bacteria (LAB) are indigenous to food-related habitats as well as associated with the mucosal surfaces of animals. The LAB family Streptococcaceae consists of the genera ...Lactococcus and Streptococcus. Members of the family include the industrially important species Lactococcus lactis, which has a long history safe use in the fermentative food industry, and the disease-causing streptococci Streptococcus pneumoniae and Streptococcus pyogenes. The central metabolic pathways of the Streptococcaceae family have been extensively studied because of their relevance in the industrial use of some species, as well as their influence on virulence of others. Recent developments in high-throughput proteomic and DNA-microarray techniques, in in vivoNMR studies, and importantly in whole-genome sequencing have resulted in new insights into the metabolism of the Streptococcaceae family. The development of cost-effective high-throughput sequencing has resulted in the publication of numerous whole-genome sequences of lactococcal and streptococcal species. Comparative genomic analysis of these closely related but environmentally diverse species provides insight into the evolution of this family of LAB and shows that the relatively small genomes of members of the Streptococcaceae family have been largely shaped by the nutritionally rich environments they inhabit.
The central metabolic pathways of the closely related genera Lactococcus and Streptococcus are reviewed with a focus on the adaptations to nutrient'rich environments.
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