Protocol for oleuropein-induced autophagy mediating drug tolerance in P. falciparum.

The anti-inflammatory activity of a phytocompound (oleuropein [OLP]) in the lipopolysaccharide (LPS)-mimicked macrophage model of inflammation demonstrates the importance of PI3K-Akt1 signaling in establishing "immune homeostasis." Here, we present a protocol for the cultivation of in vitro cultures of P. falciparum for carrying out drug sensitivity assays. We describe steps for parasite synchronization, drug treatment, DNA isolation, and starvation-induced autophagy. This protocol provides insights into autophagy and parasite tolerance to drug pressure. For complete details on the use and execution of this protocol, please refer to Sharma et al.1.

Evaluating the efficacy and safety of nivolumab and ipilimumab combination therapy compared to nivolumab monotherapy in advanced cancers (excluding melanoma): a systemic review and meta-analysis.

BACKGROUND: Nivolumab (Nivo) and ipilimumab (Ipi) have revolutionized cancer treatment by targeting different pathways. Their combination shows promising results in various cancers, including melanoma, but not all studies have demonstrated significant benefits. A meta-analysis was performed to assess the effectiveness and safety of Nivo-Ipi compared to Nivo alone in advanced cancer types (excluding melanoma). METHODS: Following PRISMA guidelines, we conducted a meta-analysis up to September 30, 2023, searching databases for randomized controlled trials (RCTs). We focused on advanced solid malignancies (excluding melanoma) with specific Nivo and Ipi dosing. Primary outcomes were overall survival (OS), progression-free survival (PFS), grades 3-4 adverse events (AEs), and treatment-related discontinuations. Secondary outcomes included specific adverse events. Statistical analysis in Review Manager included hazard ratio (HR) and risk ratio (RR), assessing heterogeneity (Higgins I2). RESULTS: Nine RCTs, involving 2152 patients covering various malignancies, were analyzed. The Nivo plus Ipi group exhibited a median OS of 12.3 months and a median PFS of 3.73 months, compared to monotherapy with 11.67 months and 3.98 months, respectively. OS showed no significant difference between Nivo and Ipi combination and Nivo alone (HR = 0.97, 95% CI: 0.88 to 1.08, p = 0.61). PFS had a slight improvement with combination therapy (HR = 0.91, 95% CI: 0.82 to 1.00, p = 0.04). Treatment-related cumulative grades 3-4 adverse events were higher with Nivo and Ipi (RR = 1.52, 95% CI: 1.30 to 1.78, p < 0.00001), as were treatment-related discontinuations (RR = 1.99, 95% CI: 1.46 to 2.70, p < 0.0001). Hepatotoxicity (RR = 2.42, 95% CI: 1.39 to 4.24, p = 0.002), GI toxicity (RR = 2.84, 95% CI: 1.44 to 5.59, p = 0.002), pneumonitis (RR = 2.29, 95% CI: 1.24 to 2.23, p = 0.008), dermatitis (RR = 2.96, 95% CI: 1.08 to 8.14, p = 0.04), and endocrine dysfunction (RR = 6.22, 95% CI: 2.31 to 16.71, p = 0.0003) were more frequent with Nivo and Ipi. CONCLUSIONS: Combining nivolumab and ipilimumab did not significantly improve overall survival compared to nivolumab alone in advanced cancers (except melanoma). However, it did show slightly better PFS at the cost of increased toxicity, particularly grades 3-4 adverse events. Specific AEs occurred more frequently in the combination group. Further trials are needed to fully assess this combination in treating advanced cancers.

Oleuropein activates autophagy to circumvent anti-plasmodial defense.

Antimalarial drug resistance and unavailability of effective vaccine warrant for newer drugs and drug targets. Hence, anti-inflammatory activity of phyto-compound (oleuropein; OLP) was determined in antigen (LPS)-stimulated human THP-1 macrophages (macrophage model of inflammation; MMI). Reduction in the inflammation was controlled by the PI3K-Akt1 signaling to establish the "immune-homeostasis." Also, OLP treatment influenced the cell death/autophagy axis leading to the modulated inflammation for extended cell survival. The findings with MII prompted us to detect the antimalarial activity of OLP in the wild type (3D7), D10-expressing GFP-Atg18 parasite, and chloroquine-resistant (Dd2) parasite. OLP did not show the parasite inhibition in the routine in vitro culture of P. falciparum whereas OLP increased the antimalarial activity of artesunate. The molecular docking of autophagy-related proteins, investigations with MMI, and parasite inhibition assays indicated that the host activated the autophagy to survive OLP pressure. The challenge model of P. berghei infection showed to induce autophagy for circumventing anti-plasmodial defenses.

Employment and working conditions of nurses: where and how health inequalities have increased during the COVID-19 pandemic?

BACKGROUND: Nurses and midwives play a critical role in the provision of care and the optimization of health services resources worldwide, which is particularly relevant during the current COVID-19 pandemic. However, they can only provide quality services if their work environment provides adequate conditions to support them. Today the employment and working conditions of many nurses worldwide are precarious, and the current pandemic has prompted more visibility to the vulnerability to health-damaging factors of nurses' globally. This desk review explores how employment relations, and employment and working conditions may be negatively affecting the health of nurses in countries such as Brazil, Croatia, India, Ireland, Italy, México, Nepal, Spain, and the United Kingdom. MAIN BODY: Nurses' health is influenced by the broader social, economic, and political system and the redistribution of power relations that creates new policies regarding the labour market and the welfare state. The vulnerability faced by nurses is heightened by gender inequalities, in addition to social class, ethnicity/race (and caste), age and migrant status, that are inequality axes that explain why nurses' workers, and often their families, are exposed to multiple risks and/or poorer health. Before the COVID-19 pandemic, informalization of nurses' employment and working conditions were unfair and harmed their health. During COVID-19 pandemic, there is evidence that the employment and working conditions of nurses are associated to poor physical and mental health. CONCLUSION: The protection of nurses' health is paramount. International and national enforceable standards are needed, along with economic and health policies designed to substantially improve employment and working conditions for nurses and work-life balance. More knowledge is needed to understand the pathways and mechanisms on how precariousness might affect nurses' health and monitor the progress towards nurses' health equity.