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Methods in Enzymology 2022Tribbles proteins are pervasive pseudokinases in cellular signaling. They play a major role in the differentiation of myeloid cells, hepatocytes and adipocytes, and more...
Tribbles proteins are pervasive pseudokinases in cellular signaling. They play a major role in the differentiation of myeloid cells, hepatocytes and adipocytes, and more widely in immune function, metabolism and cancer. Like many other pseudokinases, an inherent lack of catalytic activity has meant that a specialized cadre of techniques has been required to investigate Tribbles function. A prerequisite to most in vitro biochemistry has been robust methods for purifying useful quantities of Tribbles protein, which can sometimes exhibit non-optimal behavior upon recombinant expression. For instance, structural studies of the Tribbles family have largely focused on TRIB1, in part because of more readily available protein. Here we describe methods we have developed to routinely produce milligram quantities of TRIB1, and specific considerations when employing TRIB1 protein for various downstream analyses. Namely, we describe preparation and crystallization of TRIB1 for structural studies, and using fluorescence polarization and isothermal titration calorimetry to analyze interactions with TRIB1. We hope that applying these considerations can facilitate further understanding of TRIB1 function, specifically, and can be selectively applied to improve studies of other Tribbles proteins and pseudokinases more generally.
Topics: Cell Differentiation
PubMed: 35525548
DOI: 10.1016/bs.mie.2022.03.023 -
Frontiers in Pharmacology 2022To characterize the trend of opioid use (number of users, dispensations and oral morphine milligram equivalents) in Catalonia (Spain). This population-based cohort...
To characterize the trend of opioid use (number of users, dispensations and oral morphine milligram equivalents) in Catalonia (Spain). This population-based cohort study included all individuals aged 18 years or older, registered in the Information System for Research in Primary Care (SIDIAP), which covers >75% of the population in Catalonia, Spain, from 1 January 2007, to 31 December 2019. The exposures were all commercialized opioids and their combinations (ATC-codes): codeine, tramadol, oxycodone, tapentadol, fentanyl, morphine, and other opioids (dihydrocodeine, hydromorphone, dextropropoxyphene, buprenorphine, pethidine, pentazocine). The main outcomes were the annual figures per 1,000 individuals of 1) opioid users, 2) dispensations, and 3) oral morphine milligram equivalents (MME). Results were stratified separately by opioid types, age (5-year age groups), sex (male or female), living area (rural or urban), and socioeconomic status (from least, U1, to most deprived, U5). The overall trends were quantified using the percentage change (PC) between 2007 and 2019. Among 4,656,197 and 4,798,114 residents from 2007 to 2019, the number of opioid users, dispensations and morphine milligram equivalents per 1,000 individuals increased 12% (percentage change: 95% confidence interval (CI) 11.9-12.3%), 105% (95% confidence interval 83%-126%) and 339% (95% CI 289%-390%) respectively. Tramadol represented the majority of opioid use in 2019 (61, 59, and 54% of opioid users, dispensations, and total MME, respectively). Individuals aged 80 years or over reported the sharpest increase regarding opioid users (PC: 162%), dispensations (PC: 424%), and MME (PC: 830%). Strong opioids were increasingly prescribed for non-cancer pains over the years. Despite the modest increase of opioid users, opioid dispensations and MME increased substantially, particularly in the older population. In addition, strong opioids were incrementally indicated for non-cancer pains over the years. These findings suggest a transition of opioid prescriptions from intermittent to chronic and weak to strong and call for more rigorous opioid stewardship.
PubMed: 35754470
DOI: 10.3389/fphar.2022.912361 -
Food Research International (Ottawa,... Mar 2022Polyphenols, which are commonly found in fruits, vegetables, cereals, and legumes, are the most abundant dietary antioxidants. To date, numerous studies have... (Review)
Review
Polyphenols, which are commonly found in fruits, vegetables, cereals, and legumes, are the most abundant dietary antioxidants. To date, numerous studies have demonstrated the ability of polyphenols to prevent the development of several diseases and established the corresponding structure-activity relationships. However, polyphenol standards are either not commercially available or very expensive, mainly because the structural complexity and diversity of polyphenols complicate their fractionation and isolation from plant extracts by conventional separation techniques. High-speed countercurrent chromatography (HSCCC) is based on continuous liquid-liquid partitioning, which enables one to eliminate irreversible adsorption on solid supports. This technique has been extensively used for natural product isolation and is well suited to the effective large-scale separation of polyphenols and their derivatives, achieving high purities and yields of up to several hundred milligrams per run within several hours. The present review briefly introduces briefly HSCCC technology and summarizes its applications in the separation and purification of plant polyphenols, including the recent achievements in the large-scale preparation of proanthocyanidins and anthocyanins by our laboratory.
Topics: Anthocyanins; Antioxidants; Chromatography, High Pressure Liquid; Countercurrent Distribution; Polyphenols
PubMed: 35227478
DOI: 10.1016/j.foodres.2022.110956 -
British Journal of Anaesthesia Jul 2021Opioids have been linked to worse oncologic outcomes in surgical patients. Studies in certain cancer types have identified associations between survival and...
BACKGROUND
Opioids have been linked to worse oncologic outcomes in surgical patients. Studies in certain cancer types have identified associations between survival and intra-tumoural opioid receptor gene alterations, but no study has investigated whether the tumour genome interacts with opioid exposure to affect survival. We sought to determine whether intraoperative opioid exposure is associated with recurrence-specific survival and overall survival in early-stage lung adenocarcinoma, and whether selected tumour genomics are associated with this relationship. Associations between ketamine and dexmedetomidine and outcomes were also studied.
METHODS
Surgical patients (N=740) with pathological stage I-III lung adenocarcinoma and next-generation sequencing data were retrospectively reviewed from a prospectively maintained database.
RESULTS
On multivariable analysis, ketamine administration was protective for recurrence-specific survival (hazard ratio = 0.44, 95% confidence interval 0.24-0.80; P=0.007), compared with no adjunct. Higher intraoperative oral morphine milligram equivalents were significantly associated with worse overall survival (hazard ratio=1.09/10 morphine milligram equivalents, 95% confidence interval 1.02-1.17; P=0.010). Significant interaction effects were found between morphine milligram equivalents and fraction genome altered and morphine milligram equivalents and CDKN2A, such that higher fraction genome altered or CDKN2A alterations were associated with worse overall survival at higher morphine milligram equivalents (P=0.044 and P=0.052, respectively). In contrast, alterations in the Wnt (P=0.029) and Hippo (P=0.040) oncogenic pathways were associated with improved recurrence-specific survival at higher morphine milligram equivalents, compared with unaltered pathways.
CONCLUSIONS
Intraoperative opioid exposure is associated with worse overall survival, whereas ketamine exposure is associated with improved recurrence-specific survival in patients with early-stage lung adenocarcinoma. This is the first study to investigate tumour-specific genomic interactions with intraoperative opioid administration to modify survival associations.
Topics: Adenocarcinoma of Lung; Aged; Analgesics, Opioid; Female; Genomics; Humans; Intraoperative Care; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Pain, Postoperative; Prospective Studies; Retrospective Studies; Survival Rate
PubMed: 34147159
DOI: 10.1016/j.bja.2021.03.030 -
American Journal of Preventive Medicine May 2022Increases in opioid prescribing contributed to the opioid epidemic in the U.S. Subsequent efforts to promote safer use of opioids for treating pain included augmenting...
INTRODUCTION
Increases in opioid prescribing contributed to the opioid epidemic in the U.S. Subsequent efforts to promote safer use of opioids for treating pain included augmenting prescription drug monitoring programs and prescribing guidelines. The purpose of this study is to characterize the distribution of opioids dispensed in the U.S. by specialty.
METHODS
Data from the IQVIA National Prescription Audit were analyzed (in 2019). Prescriptions were standardized to morphine milligram equivalents using the 2018 Centers for Disease Control and Prevention conversion file. The annual number of prescriptions and total dose (morphine milligram equivalents) of opioids dispensed, overall and by specialty (provider type or physician specialty), were calculated for 2012-2017.
RESULTS
The number of prescriptions for opioids dispensed declined by 26.6% overall from 2012 to 2017. However, the number of prescriptions dispensed increased for pain medicine (8.8%) and advanced practice providers (nurse practitioners: 34.8%, physician assistants: 5.4%). Similarly, total morphine milligram equivalents for opioids dispensed declined by 28.6% from 2012 to 2017. Despite an increase in the number of prescriptions, total morphine milligram equivalents of opioids dispensed declined by nearly 20% in pain medicine. Higher total morphine milligram equivalents of dispensed opioids were observed in 2017 than in 2012 for advanced practice providers (nurse practitioners: 19.1%, physician assistants: 1.8%), although a decline in morphine milligram equivalents was observed from 2016 to 2017.
CONCLUSIONS
During a period in which prescribing interventions were expanded, opioid prescribing declined overall, although not uniformly by specialty.
Topics: Analgesics, Opioid; Drug Prescriptions; Humans; Morphine; Pain; Practice Patterns, Physicians'; Prescription Drug Monitoring Programs
PubMed: 35151524
DOI: 10.1016/j.amepre.2021.10.022 -
Angewandte Chemie (International Ed. in... Mar 2022We demonstrate catalytic organic synthesis by Resonant Acoustic Mixing (RAM): a mechanochemical methodology that does not require bulk solvent or milling media. Using as...
We demonstrate catalytic organic synthesis by Resonant Acoustic Mixing (RAM): a mechanochemical methodology that does not require bulk solvent or milling media. Using as model reactions ruthenium-catalyzed ring-closing metathesis and copper-catalyzed sulfonamide-isocyanate coupling, RAM mechanosynthesis is shown to be faster, operationally simpler than conventional ball-milling, while also providing the first example of a mechanochemical strategy for ruthenium-catalyzed ene-yne metathesis. Reactions by RAM are readily and directly scaled-up without any significant changes in reaction conditions, as shown by the straightforward 200-fold scaling-up of the synthesis of the antidiabetic drug Tolbutamide, from hundreds of milligrams directly to 30 grams.
Topics: Acoustics; Catalysis; Chemistry Techniques, Synthetic; Copper; Ruthenium
PubMed: 35138018
DOI: 10.1002/anie.202115030 -
EClinicalMedicine Dec 2021Opioid analgesics play a key role in pain management but providing access while mitigating risk of misuse and dependence remains a challenge. Tracking global consumption...
BACKGROUND
Opioid analgesics play a key role in pain management but providing access while mitigating risk of misuse and dependence remains a challenge. Tracking global consumption of all opioids over time can help identify emerging patterns and drivers of use.
METHODS
Prescription opioid analgesic consumption was estimated for 76 countries between 2009 and 2019 using IQVIA MIDAS data. We reported country-level consumption trends in morphine milligram equivalents (MMEs), assessed differences in consumption between high-income (HICs), upper-middle income (UMICs), and low- and lower-middle income countries (LMICs), and identified country-level socioeconomic drivers of consumption using fixed-effects panel regression models.
FINDINGS
Global opioid consumption rate declined from 216·3 to 151·5 morphine milligram equivalents per 1,000 inhabitants per day (MID) between 2009 and 2019, with consumption declines in the US and Germany. Overall, consumption rates increased in HICs by a median 36·6 MID (IQR, -7·5 -124·5) with substantial heterogeneity between countries. Median consumption rates were lower in UMICs (23·6 MID) and LMICs (8·3 MID) compared to HICs (345·1 MID) and increased by median 10·4 and 3·7 MID from 2009-2019, respectively. Consumption rates were associated with income (coefficient 18·84, 95% confidence interval 3·8-33·9) and trade (13·59, 1·3-25·8) in UMICs, and physician density (1·95, 1·2-2·7) in LMICs. Tramadol consumption rate increased in the study period and accounted for a relatively large proportion of total opioid volume consumed across all country-income groups.
INTERPRETATION
Substantial heterogeneity in global opioid consumption patterns reflect the challenges involved with providing adequate access to opioid treatment while avoiding potential misuse.
PubMed: 34820610
DOI: 10.1016/j.eclinm.2021.101198 -
Saudi Pharmaceutical Journal : SPJ :... Nov 2020Atorvastatin (ATO) is of the statin class and is used as an orally administered lipid-lowering drug. ATO is a reversible synthetic competitive inhibitor of... (Review)
Review
Atorvastatin (ATO) is of the statin class and is used as an orally administered lipid-lowering drug. ATO is a reversible synthetic competitive inhibitor of 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase thus leading to a reduction in cholesterol synthesis. It has recently been demonstrated that ATO has different pharmacological actions, which are unrelated to its lipid-lowering effects and has the ability to treat chronic airway diseases. This paper reviews the potential of ATO as an anti-inflammatory, antioxidant, and anti-proliferative agent after oral or inhaled administration. This paper discusses the advantages and disadvantages of using ATO under conditions associated with those found in the airways. This treatment could potentially be used to support the formulating of ATO as an inhaler for the treatment of chronic respiratory diseases.
PubMed: 33250642
DOI: 10.1016/j.jsps.2020.08.025 -
Biologicals : Journal of the... Jan 2020With the advancements in upstream technologies, the capacity for monoclonal antibody (mAb) production has transformed from a few milligrams to grams per liter. These... (Review)
Review
With the advancements in upstream technologies, the capacity for monoclonal antibody (mAb) production has transformed from a few milligrams to grams per liter. These titers lead to enormous pressure on downstream processes (DSPs), which need to be reworked to achieve higher efficiency and better utilization of available resources. Various parameters, such as column sizing, aggregate removal, filtration and volume handling, must be considered while designing a facility for commercial scale. If any of these critical parameters are not defined during the facility design stage, collapse of the process can result, further resulting in commercial loss and delaying entry of the product into the market. Therefore, during the facility design stage, the process requirements, space utilization, process efficiency and advanced manufacturing systems must be evaluated appropriately before implementation on a commercial scale.
Topics: Animals; Antibodies, Monoclonal; CHO Cells; Cricetulus; Humans
PubMed: 31558429
DOI: 10.1016/j.biologicals.2019.09.007