Cancer stem cell drugs target K-ras signaling in a stemness context

Cancer stem cells (CSCs) are considered to be responsible for treatment relapse and have therefore become a major target in cancer research. Salinomycin is the most established CSC inhibitor. However, its primary mechanistic target is still unclear, impeding the discovery of compounds with similar anti-CSC activity. Here, we show that salinomycin very specifically interferes with the activity of K-ras4B, but not H-ras, by disrupting its nanoscale membrane organization. We found that caveolae negatively regulate the sensitivity to this drug. On the basis of this novel mechanistic insight, we defined a K-ras-associated and stem cell-derived gene expression signature that predicts the drug response of cancer cells to salinomycin. Consistent with therapy resistance of CSC, 8% of tumor samples in the TCGA-database displayed our signature and were associated with a significantly higher mortality. Using our K-ras-specific screening platform, we identified several new candidate CSC drugs. Two of these, ophiobolin A and conglobatin A, possessed a similar or higher potency than salinomycin. Finally, we established that the most potent compound, ophiobolin A, exerts its K-ras4B-specific activity through inactivation of calmodulin. Our data suggest that specific interference with the K-ras4B/calmodulin interaction selectively inhibits CSC.Peer reviewe

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Estrategia de competencias gerenciales y comunicación organizacional interna en el sector hotelero de 3 y 4 estrellas de Cajamarca

TesisLa investigación tiene como objetivo determinar la relación que existe entre la estrategia de competencias gerenciales con la comunicación organizacional interna del sector hotelero de 3 y 4 estrellas de la ciudad de Cajamarca, conociendo la problemática por la que esta atraviesa puesto que no existen antecedentes de estudios de este tipo en dichas organizaciones; se formuló como hipótesis que “Existe influencia directa de la estrategia de competencias gerenciales en la comunicación organizacional interna en el Sector Hotelero de 3 y 4 estrellas de Cajamarca”. Las estrategias competitivas gerenciales se dividieron en tres áreas de análisis aspecto personal, aspecto social y aspecto laboral. Para medir las competencias gerenciales, se recogió información de 25 gerentes del sector hotelero. Luego del diagnóstico de las competencias gerenciales, se concluye que los gerentes tienen una tendencia valores medios bajos a nivel de la variable y por ende a nivel de las dimensiones. La dimensión aspecto social, el porcentaje más alto es el de 43.6%. La dimensión aspecto social, también se ubica dentro de los valores medios, el valor más elevado es de 42.4%, que se encuentra ubicada en la escala de valor medio bajo. La dimensión aspecto laboral, también se ubica dentro de los valores medios, el porcentaje más alto de esta dimensión es el de 43.2% que se ubica en la escala de valor medio bajo. La dimensión objetivos que persigue, el porcentaje más alto el de 40.3% que se sitúa en la escala de valor medio bajo; la dimensión flujos de comunicación, sus porcentajes también tienen valores medios el porcentaje más alto alcanzado es el 37.3%, en relación a la dimensión funciones de la comunicación, esta también a ha alcanzado valores medios. La correlación existente entre el competencias gerenciales y comunicación organizacional se encontró que para un nivel de confianza de 0.05 y con 100 grados de libertad, el coeficiente de correlación es de r = 0.715 y es mayor al valor del error del stándar multiplicado por la tabla t de Student siendo el valor de 0.111, resultando nuestro valor mayor que el esperado por lo tanto se rechaza la hipótesis nula y se acepta la hipótesis de investigación concluyendo que sí existe relació

Effect Of Lead Exposure On Egg Production, Quality And Hatchability In Quail Birds (Coturnix Japonica)

Thirty Quail birds (9 males and 21 females) weighing between (50-55g) and (115-125g) were divided into three groups in a ratio 3:7 as males and females maintained on normal standard diet (ECWA feeds Jos) and water ad-libitum. Birds in groups II, test I and groups III, test II were exposed to lead acetate (0.05%) at the ages of two and eight weeks (postnatal & maturity onset) respectively. The experiment lasted for 13 weeks. Fluid and feed intake was monitored daily as well as body weight gain/loss. Egg quality was determined using egg quality factors, as egg weight, shell thickness, Haugh unit, albumin index and some biochemical parameters of the egg content. No significant difference was observed in the mean fluid and feed intake in the two treatment groups compared to control group. The weekly body weight was lower in the treatment groups (T1 & T11) compared to normal control, with the test I group being more pronounced and was statistically significant (

Reliability of FAMACHA© chart for the evaluation of anaemia in goats in and around Maiduguri

The reliability of FAMACHA© chart for identifying anaemic goats was compared with Packed Cell Volume (PCV). The colour of the lower eyelids was graded with FAMACHA© chart based on FAMACHA© scores (FS) of 1-5. The animals were scored from severely anaemic (white or FS 5) through moderately anaemic (pink or FS 3) to non-anaemic (red or FS 1). The prevalence of anaemia in the animals was also determined. This study was done to control death of animals from anaemia by the use of FAMACHA© chart, a method which does not need laboratory analysis and can be used by the illiterate with minimal training. A total of 415 goats were used for the study. Blood samples were collected for determination of PCV. Data for both FS and PCV were evaluated using two separate cut off points for each sample (values of FS 4 and 5 or FS 5 and PCV values of ≤ 19% or ≤ 15 %), to determine anaemic animals. The FAMACHA© Score of the evaluated goats was normally distributed, with FS 3 occurring most frequently (34.5%), whilst, the least was FS 1 (5.3%). There was a high negative correlation between FS and PCV (r = -0.69, P < 0.02). The sensitivity of FS was high (64%) when FS 5 and PCV ≤ 19%, were used to determine anaemia, but when FS 4&5 and PCV ≤ 15% were used, the sensitivity decreased to 22%. Thus, it was concluded that FAMACHA© scores of 5 gave the most reliable indicator of anaemia in goats, coinciding with the PCV values of ≤ 19%. A high Likelihood Ratio of 22 was recorded in this study. Indicating that FS will be positive for anaemia 22 times in anaemic animals than in non anaemic animals.Keywords: Anaemia, FAMACHA© chart, Goat, Reliability, Sensitivit