Investigations into hydrogen sulfide (H2S) signaling pathways have demonstrated both the generation and importance of persulfides, which are reactive sulfur species that contain both reduced and ...oxidized sulfur. These observations have led researchers to suggest that oxidized sulfur species, including sulfane sulfur (S0), are responsible for many of the physiological phenomena initially attributed to H2S. A common method of introducing S0 to biological systems is the administration of organic polysulfides, such as diallyl trisulfide (DATS). However, prior reports have demonstrated that commercially-available DATS often contains a mixture of polysulfides, and furthermore a lack of structure-activity relationships for organic polysulfides has limited our overall understanding of different polysulfides and their function in biological systems. Advancing our interests in the chemical biology of reactive sulfur species including H2S and S0, we report here our investigations into the rates and quantities of H2S release from a series of synthetic, pure benzyl polysulfides, ranging from monosulfide to tetrasulfide. We demonstrate that H2S is only released from the trisulfide and tetrasulfide, and that this release requires thiol-mediated reduction in the presence of cysteine or reduced glutathione. Additionally, we demonstrate the different effects of trisulfides and tetrasulfides on cell proliferation in murine epithelial bEnd.3 cells.
•A series of benzyl (poly)sulfides with 1–4 sulfur atoms is prepared.•Rates of H2S release after treatment with Cys and GSH are reported.•H2S is only released from tri- and tetra-sulfides, but not mono- or di-sulfides.•The effects of trisulfides and tetrasulfides on cell proliferation in bEnd.3 cells are reported.
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An organotetrasulfide consists of a linear chain of four sulfur atoms that could accept up to 6 e− in reduction reactions, thus providing a promising high‐capacity electrode material. Herein, we ...study three bis(aryl) tetrasulfides as cathode materials in lithium batteries. Each tetrasulfide exhibits two major voltage regions in the discharge. The high voltage slope region is governed by the formation of persulfides and thiolates, and the low voltage plateau region is due to the formation of Li2S2/Li2S. Based on theoretical calculations and spectroscopic analysis, three reduction reaction processes are revealed, and the discharge products are identified. Lithium half cells with tetrasulfide catholytes deliver high specific capacities over 200 cycles. The effects of the functional groups on the electrochemical characteristics of tetrasulfides are investigated, which provides guidance for developing optimum aryl polysulfides as cathode materials for high energy lithium batteries.
Three bis(aryl) tetrasulfides have been studied as cathode materials in rechargeable lithium batteries. Based on theoretical calculations and spectroscopic analysis, three reduction reaction processes are revealed, and the discharge products are identified. Lithium half‐cells with tetrasulfide catholytes deliver high specific capacities over 200 cycles. The effects of the functional groups on the electrochemical characteristics of tetrasulfides are investigated.
Background
Immunotherapy increases overall response rate (ORR) and overall survival (OS) in patients with non-small-cell lung cancer (NSCLC). Prognostic and predictive factors are a high need.
...Patients and methods
Retrospective review of NSCLC patients treated with nivolumab was performed. Analyzed variables included age, sex, stage, performance status (PS), location of metastases, presence of tumour-related symptoms and comorbidities, number of metastasis locations, previous chemotherapy, anti-angiogenic and radiotherapy treatments, and analytical data from the standard blood count and biochemistry.
Results
A total of 175 patients were included. Median age was 61.5 years, 73.1% were men, 77.7% were ECOG-PS 0–1, and 86.7% were included with stage IV disease. Histology was non-squamous in 77.1%. Sixty-five received nivolumab in second line (37.1%). Thirty-eight patients had brain metastasis (22%), and 39 (22.3%) liver metastasis and 126 (72%) had more than one metastatic location. The ORR was 15.7% with median Progression free survival (PFS) 2.8 months and median OS 5.81 months. Stage III vs IV and time since the beginning of the previous line of treatment ≥ 6 vs < 6 months were associated with better response. PS 2, time since the previous line of treatment < 6 vs ≥ 6 months, and more than one metastatic location were independently associated with shorter OS in multivariable analysis (7.8 vs 2.7 months, 11.2 vs 4.6 months, and 9.4 vs 5.1 month). Finally, time since the previous treatment < 6 vs ≥ 6 months and more than one metastatic location were independently associated with shorter PFS in multivariable analysis (4.3 vs 2.3 months and 4.7 vs 2.3 months).
Conclusion
Poor PS, short period of time since the previous treatment, and more than one metastatic location were associated with poorer prognostic.
Modification of the tubulin‐microtubule (Tub‐Mts) system has generated effective strategies for developing different treatments for cancer. A huge amount of clinical data about inhibitors of the ...tubulin‐microtubule system have supported and validated the studies on this pharmacological target. However, many tubulin‐microtubule inhibitors have been developed from representative and common scaffolds that cover a small region of the chemical space with limited structural innovation. The main goal of this study is to develop the first consensus virtual screening protocol for natural products (ligand‐ and structure‐based drug design methods) tuned for the identification of new potential inhibitors of the Tub‐Mts system. A combined strategy that involves molecular similarity, molecular docking, pharmacophore modeling, and in silico ADMET prediction has been employed to prioritize the selections of potential inhibitors of the Tub‐Mts system. Five compounds were selected and further studied using molecular dynamics and binding energy predictions to characterize their possible binding mechanisms. Their structures correspond to 5‐2‐(4‐hydroxy‐3‐methoxyphenyl) ethyl‐2,3‐dimethoxyphenol (1), 9,10‐dihydro‐3,4‐dimethoxy‐2,7‐phenanthrenediol (2), 2‐(3,4‐dimethoxyphenyl)‐5,7‐dihydroxy‐6‐methoxy‐4H‐1‐benzopyran‐4‐one (3), 13,14‐epoxyparvifoline‐4’,5’,6’‐trimethoxybenzoate (4), and phenylmethyl 6‐hydroxy‐2,3‐dimethoxybenzoate (5). Compounds 1–3 have been associated with literature reports that confirm their activity against several cancer cell lines, thus supporting the utility of this protocol.
Rebaudioside A (Reb A) is a diterpenoid isolated from the leaves of Stevia rebaudiana (Bertoni) that has been shown to possess pharmacological activity, including anti‐inflammatory and antioxidant ...properties. However, the ability of Reb A to prevent liver injury has not been evaluated. Therefore, we aimed to study the potential of Reb A (20 mg/kg; two times daily intraperitoneally) to prevent liver injury induced by thioacetamide (TAA) administration (200 mg/kg; three times per week intraperitoneally). In addition, cocultures were incubated with either lipopolysaccharide or ethanol. Antifibrotic, antioxidant and immunological responses were evaluated. Chronic TAA administration produced considerable liver damage and distorted the liver parenchyma with the presence of prominent thick bands of collagen. In addition, TAA upregulated the expression of α‐smooth muscle actin, transforming growth factor‐β1, metalloproteinases 9, 2 and 13, and nuclear factor kappaB and downregulated nuclear erythroid factor 2. Reb A administration prevented all of these changes. In cocultured cells, Reb A prevented the upregulation of genes implicated in fibrotic and inflammatory processes when cells were exposed to ethanol and lipopolysaccharide. Altogether, our results suggest that Reb A prevents liver damage by blocking oxidative processes via upregulation of nuclear erythroid factor 2, exerts immunomodulatory effects by downregulating the nuclear factor‐κB system and acts as an antifibrotic agent by maintaining collagen content.
Rebaudioside A (Reb A) has been shown to possess pharmacological activity. Therefore, we aimed to study Reb A to prevent liver injury induced by thioacetamide administration. In addition, cocultures were incubated with either lipopolysaccharide or ethanol. Antifibrotic, antioxidant and immunological responses were evaluated. Hepatotoxins upregulated the expression of several genes and protein implicated in liver fibrosis. Reb A administration prevented all these changes. Our results suggest that Reb A has a multitarget mechanism in liver fibrosis prevention.
Inhibiting the tubulin-microtubules (Tub-Mts) system is a classic and rational approach for treating different types of cancers. A large amount of data on inhibitors in the clinic supports Tub-Mts as ...a validated target. However, most of the inhibitors reported thus far have been developed around common chemical scaffolds covering a narrow region of the chemical space with limited innovation. This manuscript aims to discuss the first activity landscape and scaffold content analysis of an assembled and curated cell-based database of 851 Tub-Mts inhibitors with reported activity against five cancer cell lines and the Tub-Mts system. The structure-bioactivity relationships of the Tub-Mts system inhibitors were further explored using constellations plots. This recently developed methodology enables the rapid but quantitative assessment of analog series enriched with active compounds. The constellations plots identified promising analog series with high average biological activity that could be the starting points of new and more potent Tub-Mts inhibitors.
Background Retinopathy of prematurity is an adverse outcome of preterm birth and is a leading cause of childhood blindness. The relationship between the subtypes of preterm birth with retinopathy of ...prematurity is understudied. Objective To investigate whether there is a difference in the incidence of type 1 or type 2 retinopathy of prematurity in infants with preterm birth resulting from spontaneous preterm labor, a medical indication of preterm birth, or preterm premature rupture of the membranes. Study Design A retrospective cohort study was conducted of 827 infants screened for retinopathy of prematurity who were delivered at a single tertiary care center in Colorado. All infants fulfilled the American Academy of Pediatrics 2013 screening criteria for retinopathy of prematurity defined as “infants with a birth weight of ≤1500 g or gestational age of 30 weeks or less (as defined by the attending neonatologist) and selected infants with a birth weight between 1500 and 2000 g or gestational age of >30 weeks with an unstable clinical course, including those requiring cardiorespiratory support and who are believed by their attending pediatrician or neonatologist to be at high risk for retinopathy of prematurity.” Two independent reviewers masked to retinopathy of prematurity outcomes determined whether preterm birth resulted from spontaneous preterm labor, medical indication of preterm birth, or preterm premature rupture of the membranes. Discrepancies were resolved by a third reviewer. Data were analyzed with univariate and multivariable logistic regression. Results In our cohort, the frequency of preterm birth resulting from spontaneous preterm labor, medical indication of preterm birth, or preterm premature rupture of the membranes was 34%, 40%, and 26%, respectively. The mean gestational age (weeks, days) ± SD (range) in the cohort and across the preterm birth subtypes was as follows: entire cohort, 28 weeks, 6 days ± 2 weeks, 3 days (23 weeks, 3 days – 36 weeks, 4 days); spontaneous preterm labor, 28 weeks 1 day ± 2 weeks, 3 days (23 weeks, 3 days – 33 weeks, 4 days); medical indication of preterm birth, 29 weeks, 1 day ± 2 weeks, 2 days (24–36 weeks, 4 days); preterm premature rupture of the membranes, 28 weeks, 4 days ± 2 weeks, 1 day (24–33 weeks, 1 day). Among infants with type 1, type 2, or no retinopathy of prematurity, the incidence of type 1 or type 2 retinopathy of prematurity in births from spontaneous preterm labor, medical indication of preterm birth, and preterm premature rupture of the membranes was 37 of 218 (17%), 27 of 272 (10%), and 10 of 164 (6%), respectively. Adjusted for gestational age, birth weight, and multiparity and compared with the preterm premature rupture of the membranes group, the odds ratios of spontaneous preterm labor and medical indication of preterm birth for type 1 or type 2 retinopathy of prematurity were 6.1 (95% confidence interval, 1.8 to 20, P = .003) and 5.5 (95% confidence interval, 1.4 to 21, P = .01), respectively. Among neonates born after preterm premature rupture of the membranes, the probability of developing type 1 or type 2 retinopathy of prematurity was greatest in infants with rupture of membrane duration of up to 24 hours. After 24 hours, the probability of developing type 1 or type 2 retinopathy of prematurity declined. The odds of developing type 1 or type 2 retinopathy of prematurity was 9.0 (95% confidence interval 2.3 to 34, P = .002) in infants who had preterm premature rupture of the membranes ≤ 24 hours compared with infants who had preterm premature rupture of the membranes > 24 hours. Conclusion Type 1 or type 2 retinopathy of prematurity are adverse ocular outcomes linked with not only lower gestational age and birth weight at delivery but also with events in the intrauterine environment that trigger a preterm birth. The reduced incidence of type 1 or type 2 retinopathy of prematurity in the preterm premature rupture of the membranes group compared with other causes of preterm birth may be related to the perinatal therapies associated with preterm premature rupture of the membranes (such as corticosteroids, antibiotics, maternal–fetal surveillance), which may have an inhibitory effect on the development of retinopathy of prematurity. We suggest that the physiologic events that predispose infants to type 1 or type 2 retinopathy of prematurity begin before delivery.
Research Objective
The opioid epidemic in the United States remains a growing public health problem. Understanding opioid prescribing for children, adolescents, and young adults is essential for ...developing targeted interventions and policies at both national and local levels for this population. In this study, we investigate temporal trends in opioid‐prescribing practices in children, adolescents, and young adults in the United States from 2006 to 2018.
Study Design
Cross‐sectional analysis of opioid prescriptions from retail pharmacies. Primary outcomes included total number of opioid prescriptions, duration of prescription (overall mean, ≤3 days, and ≥30 days), amount prescribed in mean morphine milligram equivalents (MME) dispensed per day, and high‐dose prescriptions (prescriptions for doses >90 MME/day for those >14 years). Yearly values were reported overall and stratified by age for 2006, 2012, and 2018, with relative percentage change between point estimates for 2006 and 2018.
Population Studied
Opioid prescription data from January 1, 2006, to December 31, 2018, for children, adolescents, and young adults <25 years were extracted from the IQVIA XPonent database which accounts for 90% of retail outpatient prescriptions in the United States.
Principal Findings
The opioid prescription rate (per 100 persons) decreased by 58.9% overall from 2006 to 2018, declining from a rate of 4.6‐1.4 for children 0‐5 years, 4.3‐1.4 for those 6‐9 years, 6.6‐2.7 for those 10‐14 years, 20.4‐10.8 for adolescents 15‐19 years, and 35.1‐15.3 for young adults 20‐24 years. The total MME/day was 36.5 in 2006, 34.4 in 2012, and 31.2 in 2018 (decrease of 14.7% by 2018), with decreased amounts prescribed in all ages, except those ≤5 years. The total mean opioid prescription duration remained relatively stable, with duration of 6 days in 2006, 6.8 days in 2012, and 6.2 days in 2018. The number of prescriptions with duration ≤3 days was unchanged, but the number of prescriptions with duration ≥30 days increased by 31.8%, with the largest increases in children <15 years. High‐dose prescriptions for the 15‐24 years cohort decreased by >50% between 2006 and 2018.
Conclusions
Since 2006, total opioid prescriptions have decreased for children, adolescents, and young adults, and there has been a reduction in the prescription amount and in high‐dose opioid prescriptions for adolescents and young adults. However, despite current opioid‐prescribing guidelines, as well as policies that limit days’ supply, opioids continue to be frequently dispensed and opioid prescriptions with duration ≥30 days have increased.
Implications for Policy or Practice
Continued policy efforts and the development of clinical practice guidelines for youths are necessary to ensure safe and judicious opioid prescribing for children, adolescents, and young adults. Further study, including investigating geographic patterns and patient‐ and prescriber‐level characteristics, will help inform targeted interventions for appropriate prescribing practices in this population.
Two samples of Cu2S–FeS mixtures were prepared in order to study the thermal oxidation evolution of the raw materials used during the first and second sub-stages of slag blowing in a converter ...furnace. To determine the thermal evolution in an oxidative environment, thermogravimetric analysis (TGA) was performed on both samples at four linear heating ramps (5, 10, 15 and 20 °C min−1), obtaining similar curves in both cases. Of the methods studied, Friedman, Coats-Redfern, Flynn-Wall-Ozawa and Kissinger-Akahira-Sunose, the latter was found to be the most suitable to represent the oxidative evolution of Cu2S–FeS mixtures. The kinetic parameters calculated using Kissinger-Akahira-Sunose method are highly dependent on the degree of conversion. The results obtained for the activation energy ranging between 10 and 20 Kj mol−1 for conversion rates of 0.2, and between 30 and 50 Kj mol−1 for conversion rates of 0.9. In addition, a thermodynamic computational model was developed to determine the reactions taking place during the oxidation of the Cu2S–FeS mixtures.
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•Thermal oxidation evolution of Cu2S–FeS mixtures has been studied by thermogravimetry.•Among the methods studied for kinetic analysis, KAS method appears the most suitable.•TGA curve of Cu2S–FeS has been reproduced by computational thermodynamic calculations.•The chemical reactions involved in the oxidation of Cu2S–FeS have been determined.
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