Chemical screening identifies the β-Carboline alkaloid harmine to be synergistically lethal with doxorubicin.

Despite being an invaluable chemotherapeutic agent for several types of cancer, the clinical utility of doxorubicin is hampered by its age-related and dose-dependent cardiotoxicity. Co-administration of dexrazoxane as a cardioprotective agent has been proposed, however recent studies suggest that it attenuates doxorubicin-induced antitumor activity. Since compounds of natural origin present a rich territory for drug discovery, we set out to identify putative natural compounds with the view to mitigate or minimize doxorubicin cardiotoxicity. We identify the DYRK1A kinase inhibitor harmine, which phosphorylates Tau that is deregulated in Alzheimer's disease, as a potentiator of cell death induced by non-toxic doses of doxorubicin. These observations suggest that harmine or other compounds that target the DYRK1A kinase my offer a new therapeutic opportunity to suppress doxorubicin age-related and dose-dependent cardiotoxicity

Impacts of dietary inclusion of dried brewers’ grains on growth, carcass traits, meat quality, nutrient digestibility and blood biochemical indices of broilers

The current investigation aimed to evaluate the effect of dietary inclusion of dried brewers’ grains (DBG) on growth performance, carcass traits, meat quality, nutrient digestibility, blood biochemical constituents and antioxidant indices of broiler chickens. A total of 300 unsexed one-week-old Hubbard chicks were randomly allotted to five treatment groups. The dietary treatments consisted of a basal diet as the control and DBG groups (3%, 6%, 9% and 12%, respectively). The best feed conversion ratio (FCR) was found in the group of birds fed a diet containing 9% DBG, compared the other groups. Dressing and abdominal fat percentages decreased significantly but gradually with the elevated DBG level in the diets from 6% to 12%. The inclusion of DBG in broiler diets resulted in significant positive effects on all of the sensory evaluation indicators except appearance and tenderness. Broilers fed a diet containing 3% DBG had significant higher of digestion coefficients for crude protein than those fed on the other experimental diets. Based on growth performance and health status, 3% or 9% DBG may be the optimum percentages for inclusion in the diets of poultry until six weeks old. In addition, DBG exerted several health benefits in meat, which would be reflected positively on human health.Keywords: unconventional feedstuff, inclusion, performance, chicken, meat qualit

High temperature drives topoisomerase mediated chromosomal break repair pathway choice

Cancer-causing mutations often arise from inappropriate DNA repair, yet acute exposure to DNA damage is widely used to treat cancer. The challenge remains in how to specifically induce excessive DNA damage in cancer cells while minimizing the undesirable effects of genomic instability in noncancerous cells. One approach is the acute exposure to hyperthermia, which suppresses DNA repair and synergizes with radiotherapy and chemotherapy. An exception, however, is the protective effect of hyperthermia on topoisomerase targeting therapeutics. The molecular explanation for this conundrum remains unclear. Here, we show that hyperthermia suppresses the level of topoisomerase mediated single- and double-strand breaks induced by exposure to topoisomerase poisons. We further uncover that, hyperthermia suppresses hallmarks of genomic instability induced by topoisomerase targeting therapeutics by inhibiting nuclease activities, thereby channeling repair to error-free pathways driven by tyrosyl-DNA phosphodiesterases. These findings provide an explanation for the protective effect of hyperthermia from topoisomerase-induced DNA damage and may help to explain the inverse relationship between cancer incidence and temperature. They also pave the way for the use of controlled heat as a therapeutic adjunct to topoisomerase targeting therapeutics

High Temperature Drives Topoisomerase Mediated Chromosomal Break Repair Pathway Choice.

YesCancer-causing mutations often arise from inappropriate DNA repair, yet acute exposure to DNA damage is widely used to treat cancer. The challenge remains in how to specifically induce excessive DNA damage in cancer cells while minimizing the undesirable effects of genomic instability in noncancerous cells. One approach is the acute exposure to hyperthermia, which suppresses DNA repair and synergizes with radiotherapy and chemotherapy. An exception, however, is the protective effect of hyperthermia on topoisomerase targeting therapeutics. The molecular explanation for this conundrum remains unclear. Here, we show that hyperthermia suppresses the level of topoisomerase mediated single- and double-strand breaks induced by exposure to topoisomerase poisons. We further uncover that, hyperthermia suppresses hallmarks of genomic instability induced by topoisomerase targeting therapeutics by inhibiting nuclease activities, thereby channeling repair to error-free pathways driven by tyrosyl-DNA phosphodiesterases. These findings provide an explanation for the protective effect of hyperthermia from topoisomerase-induced DNA damage and may help to explain the inverse relationship between cancer incidence and temperature. They also pave the way for the use of controlled heat as a therapeutic adjunct to topoisomerase targeting therapeutics

Angular momenta creation in relativistic electron-positron plasma

Creation of angular momentum in a relativistic electron-positron plasma is explored. It is shown that a chain of angular momentum carrying vortices is a robust asymptotic state sustained by the generalized nonlinear Schrodinger equation characteristic to the system. The results may suggest a possible electromagnetic origin of angular momenta when it is applied to the MeV epoch of the early Universe.Comment: 20 pages, 6 figure

Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Background: In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). Findings: Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p<0·0001). Interpretation: In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

Background: Many patients with COVID-19 have been treated with plasma containing anti-SARS-CoV-2 antibodies. We aimed to evaluate the safety and efficacy of convalescent plasma therapy in patients admitted to hospital with COVID-19. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. The trial is underway at 177 NHS hospitals from across the UK. Eligible and consenting patients were randomly assigned (1:1) to receive either usual care alone (usual care group) or usual care plus high-titre convalescent plasma (convalescent plasma group). The primary outcome was 28-day mortality, analysed on an intention-to-treat basis. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Findings: Between May 28, 2020, and Jan 15, 2021, 11558 (71%) of 16287 patients enrolled in RECOVERY were eligible to receive convalescent plasma and were assigned to either the convalescent plasma group or the usual care group. There was no significant difference in 28-day mortality between the two groups: 1399 (24%) of 5795 patients in the convalescent plasma group and 1408 (24%) of 5763 patients in the usual care group died within 28 days (rate ratio 1·00, 95% CI 0·93–1·07; p=0·95). The 28-day mortality rate ratio was similar in all prespecified subgroups of patients, including in those patients without detectable SARS-CoV-2 antibodies at randomisation. Allocation to convalescent plasma had no significant effect on the proportion of patients discharged from hospital within 28 days (3832 [66%] patients in the convalescent plasma group vs 3822 [66%] patients in the usual care group; rate ratio 0·99, 95% CI 0·94–1·03; p=0·57). Among those not on invasive mechanical ventilation at randomisation, there was no significant difference in the proportion of patients meeting the composite endpoint of progression to invasive mechanical ventilation or death (1568 [29%] of 5493 patients in the convalescent plasma group vs 1568 [29%] of 5448 patients in the usual care group; rate ratio 0·99, 95% CI 0·93–1·05; p=0·79). Interpretation: In patients hospitalised with COVID-19, high-titre convalescent plasma did not improve survival or other prespecified clinical outcomes. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Productive performance, fertility and hatchability, blood indices and gut microbial load in laying quails as affected by two types of probiotic bacteria

This study investigated two kinds of probiotic bacteria (Bacillus toyonensis, B1 and Bifidobacterium bifidum, B2) on laying Japanese quail’s performance, egg quality, fertility and hatchability, blood biochemical characteristics and microbiological parameters. A total of 270 mature quails (180 females and 90 males) were distributed into ten groups in a completely randomized design at eight weeks of age. The experimental groups were as follows: T1: basal diet only (control); T2-T5, basal diet plus 0.05, 0.075, 0.10 and 0.125% B1, respectively; T6: basal diet plus 0.10% B2; T7-T10: basal diet plus 0.05, 0.075, 0.10 and 0.125% B1 plus 0.05% B2, respectively. Results revealed that egg number (EN) and egg weight (EW) were gradually increased (P < 0.01) as the levels of both probiotic types increased. The feed conversion ratio (FCR) was significantly (P < 0.05) better within the total experimental period (8–20 weeks) due to B1 alone or/with B2 supplementation. Values of yolk percentage (Y%) were statistically (P < 0.01) higher only at 8–20 weeks of age and T10 recorded the highest value. By increasing the level of probiotics, fertility and hatchability percentages (F% and H%) were gradually increased (P < 0.01 and P < 0.05). Creatinine (CR) level was statistically reduced in birds fed T4 diet. Also, urea-N and aspartate aminotransferase (AST) levels were reduced in treated birds. The opposite was found regarding alkaline phosphatase (ALP). Conclusively, using B1 and B2 enhanced the productive performance, some egg quality traits, fertility and hatchability, digestive enzyme activities, and reduced the harmful bacteria in the gut of laying Japanese quail. Our findings could recommend to apply T4 (basal diet + 0.10 % B1), T6 (basal diet + 0.10% B2) and T9 (basal diet + 0.10% B1 + 0.05% B2) levels for the best results