In the past decade, targeted therapies for solid tumors, including non-small cell lung cancer (NSCLC), have advanced significantly, offering tailored treatment options for patients. However, individuals without targetable mutations pose a clinical challenge, as they may not respond to standard treatments like immune-checkpoint inhibitors (ICIs) and novel targeted therapies. While the mechanism of action of ICIs seems promising, the lack of a robust response limits their widespread use. Although the expression levels of programmed death ligand 1 (PD-L1) on tumor cells are used to predict ICI response, identifying new biomarkers, particularly those associated with the tumor microenvironment (TME), is crucial to address this unmet need. Recently, inflammatory cytokines such as interleukin-1 beta (IL-1β) have emerged as a key area of focus and hold significant potential implications for future clinical practice. Combinatorial approaches of IL-1β inhibitors and ICIs may provide a potential therapeutic modality for NSCLC patients without targetable mutations. In this review, we discuss the role of IL-1β in NSCLC, its involvement in inflammatory pathways, and explore its potential role in the treatment of NSCLC.

We previously described a model of deep intrinsic resistance of breast cancer wherein we used a function-based approach to selection of cancer cells that can survive a variety of challenges in prolonged but reversible quiescence. Our experimental results suggested that resistant cancer cells possess a variety of mechanisms, including modifications of the epigenome and transcriptome, for generating a high degree of cellular heterogeneity. In the present study, we evaluated JIB-04, a small-molecule epigenetic inhibitor initially discovered to inhibit cancer growth, to determine its ability to affect deep intrinsic resistance in our breast cancer model. We found that long pretreatment with JIB-04 sensitized resistant triple-negative inflammatory breast cancer cells and their parental cell line SUM149 to the chemotherapeutic drugs doxorubicin and paclitaxel. Resistant cancer cells derived from another inflammatory breast cancer cell line, FC-IBC02, were considerably more sensitive to JIB-04 than was the parental cell line. Investigating a mechanism of sensitization, we found that JIB-04 exposure increased the expression of PD-L1 in resistant cells, suggesting that JIB-04 may also sensitize resistant breast cancer cells to anti-PD-L1 immune therapy. Finally, these results support the usefulness of our experimental strategy for evaluating anticancer agents such as JIB-04 that may halt cancer evolution and prevent development of cancer resistance to currently used therapies.

The emergence of acquired resistance to EGFR-TKIs is almost inevitable even after a remarkable clinical response. Secondary mutations such as T790M and C797S are responsible for the resistance to 1st/2nd generation (1/2G) TKIs and 3G TKIs, respectively. To overcome both the T790M and C797S mutations, novel 4G EGFR-TKIs are now under early clinical development. In this study, we evaluated the efficacy of a 4G EGFR-TKI in the treatment of lung cancer with EGFR mutation as well as explored resistance mechanisms to a 4G TKI. First, we compared the efficacies of seven TKIs including a 4G TKI, BI4020, against Ba/F3 cell models that simulate resistant tumors after frontline osimertinib treatment failure because of a secondary mutation. We also established acquired re-sistant cells to BI4020 by chronic drug exposure. Ba/F3 cells with an osimertinib-resistant secondary mutation were refractory to all 3G TKIs tested (alflutinib, lazertinib, rezivertinib, almonertinib, and befotertinib). BI4020 inhibited the growth of C797S-positive cells; however it was not effective against L718Q-positive cells. Erlotinib was active against all Ba/F3 cells tested. In the analysis of resistance mechanisms of BI4020 resistant (BIR) cells, none harbored secondary EGFR mutations. HCC827BIR cells had MET gene amplification and were sensitive to a combination of capmatinib (MET-TKI) and BI4020. HCC4006BIR and H1975BIR cells exhibited epithelial to mesenchymal transition. This study suggests that erlotinib may be more suitable than 4G TKIs to overcome sec-ondary mutations after front-line osimertinib. We found that off-target mechanisms that cause re-sistance to earlier generation TKIs will also cause resistance to 4G TKIs.

Background. Azithromycin (AZM) is widely used in cystic fibrosis (CF) treatment following clinical trials demonstrating improved lung function and fewer pulmonary exacerbations. While the precise mechanisms remain elusive, immunomodulatory actions are thought to be involved. We previously reported impaired phagocytosis and defective anti-inflammatory M2 macrophage polarization in CF macrophages. This study systematically analyzed the effect of AZM on the functions of unpolarized and M1/M2 polarized macrophages in CF. Methods: Monocytes, isolated from the venous blood of patients with CF (pwCF) and healthy controls (HCs) were differentiated into monocyte-derived macrophages (MDMs) and infected with P. aeruginosa. P. aeruginosa uptake and killing by MDMs in the presence or absence of AZM was studied. M1 and M2 macrophage polarizations were induced and their functions and cytokine release were analyzed. Results: Following AZM treatment, both HC and CF MDMs exhibited a significant increase in P. aeruginosa uptake and killing, however, lysosomal acidification remained unchanged. AZM treatment led to higher activation of ERK1/2 in both HC and CF MDMs. Pharmacological inhibition of ERK1/2 using U0126 significantly reduced P. aeruginosa uptake in HC MDMs. M1 macrophage polarization remained unaffected, however, AZM treatment led to increased IL-6 and IL-10 release in both HC and CF M1 macrophages. AZM also significantly increased the phagocytic index for both pHrodo E. coli and S. aureus in CF M1 macrophages. In CF, AZM treatment promoted anti-inflammatory M2 macrophage polarization, with an increased percentage of CD209+ M2 macrophages, induction of the M2 gene CCL18, along with its secretion in the culture supernatant. However, AZM did not restore endocytosis in CF, another essential feature of M2 macrophages. Conclusions: This study highlights the cellular functions and molecular targets of AZM which may involve improved uptake of both gram-positive and gram-negative bacteria, restored anti-inflammatory macrophage polarization in CF. This may in turn shape the reduced lung inflammation observed in clinical trials. In addition, we confirmed the role of ERK1/2 activation for bacterial uptake.

A single Cancer immunotherapy has ushered in a transformative era in oncology, bringing forth unprecedented promise and opportunities. However, even with its significant breakthroughs, the domain faces the continual issue of treatment resistance. Such resistance not only restricts the broad effectiveness of these pioneering treatments but also highlights the imperative need for further research. Delving into the complex world of cancer immunotherapy resistance, we identify a range of mechanisms, from primary and secondary resistance to the notable effects of genetic and epigenetic variables, and the pivotal importance of the tumor microenvironment (TME). Additionally, we emphasize the need for innovative strategies to mitigate this resistance, including combination treatments, customized immune checkpoints, and instantaneous monitoring. By advocating for these cutting-edge methods, we foresee a direction that incorporates personalized healthcare, enhanced treatment options, and a steadfast dedication to the welfare of patients. Through a comprehensive and diverse approach, we aim to address the hurdles posed by resistance, elevating cancer immunotherapy as a symbol of hope for patients worldwide.

Abstract: Extensive research shows nurses’ work environment to be particularly stressful. This study develops, explores, and psychometrically tests a new profession specific ques-tionnaire identifying generalized and specific resistance resources, that make it possible to measure resources to manage work-related stress. An exploratory study design was em-ployed. The questionnaire was developed inspired by the MEASURE approach and the salutogenic theory of health. Building on the results from a literature review of nursing re-search and salutogenesis, supplemented by twelve interviews with hospital nurses, an item pool was generated. A first version was pilot tested in a group of nurses who were studying to become specialist nurses. A second version of the questionnaire was psycho-metrically tested on nurses in close patient care (n = 475), analysed using Principal Com-ponent Analysis as the extracting technique to identify the underlying structure of the questionnaire. The Principal Component Analysis revealed a four-component model of 19 items. “Manageability as a resource for handling the workload” was the strongest compo-nent, accounting for 21 % of the explained variance. “Contacts with patients as resources for nurses’ job satisfaction” (17.8 %). “Professional attitudes are labelled as resources to nursing” (15 %). “Colleagues are important resources for remaining in the nursing profes-sion” (11 %). The structure of the questionnaire indicates its usefulness in clinical practice for measuring resistance resources.

Durability monitoring of insecticide-treated nets (ITNs) containing a pyrethroid in combination with a second active ingredient (AI) must be adapted so that the insecticidal bioefficacy of each AI can be monitored independently. An effective way to do this is to measure rapid knock down of a pyrethroid-susceptible strain of mosquitoes to assess the bioefficacy of the pyrethroid component and to use a pyrethroid-resistant strain to measure the bioefficacy of the second ingredient. To allow robust comparison of results across tests within and between test facilities, and over time, protocols for bioefficacy testing must include either characterisation of the resistant strain, standardisation of the mosquitoes used for bioassays, or a combination of the two. Through a series of virtual meetings, key stakeholders and practitioners explored different approaches to achieving these goals. Via an iterative process we decided on the preferred approach and produced a protocol consisting of characterising mosquitoes used for bioefficacy testing before and after a round of bioassays, for example at each time point in a durability monitoring study. We present the final protocol and justify our approach to establishing a standard methodology for durability monitoring of ITNs containing pyrethroid and a second AI.

Despite available global efforts and funding, Tuberculosis (TB) continues to affect a considerable number of patients worldwide. Policy makers and stakeholders set clear goals to reduce TB incidence and mortality, but the emergence of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) complicate the reach of these goals. Drug-resistance TB needs to be diagnosed rapidly and accurately to effectively treat patients, prevent the transmission of MDR-TB, minimise mortality, reduce treatment costs and avoid unnecessary hospitalisations. In this narrative review, we provide a comprehensive overview of laboratory methods for detecting drug resistance in MTB, focusing on phenotypic, molecular and other drug susceptibility testing (DST) techniques. We found a large variety of methods used, with the BACTEC MGIT 960 being the most common phenotypic DST and the Xpert MTB/RIF being the most common molecular DST. We emphasise the importance of integrating phenotypic and molecular DST to address issues like resistance to new drugs, heteroresistance, mixed infections and low-level resistance mutations. Notably, most of the analysed studies adhered to the outdated definition of XDR-TB and did not consider the pre-XDR definition, thus posing challenges in aligning diagnostic methods with the current landscape of TB resistance.

Inflammatory bowel diseases, which consist of chronic inflammatory conditions of the colon and the small intestine, are considered a global disease of our modern society. Recently, the interest toward the use of herbal therapies for the management of inflammatory bowel diseases has increased because of their effectiveness and favorable safety profile, compared to conventional drugs. Boswellia serrata Roxb. and Curcuma longa L. are amongst the most promising herbal drugs, however, their clinical use in inflammatory bowel diseases is limited and little is known on their mechanism of action. The aim of this work was to investigate the effects of two phytochemically characterized extracts of B. serrata and C. longa in an in vitro model of intestinal inflammation. Their impact on cytokine release and reactive oxygen species production, as well as the maintenance of the intestinal barrier function and on intestinal mucosa immune cells infiltration, has been evaluated. The extracts showed a good protective effect on the intestinal epithelium at 1 µg/ml, with TEER values increasing by approximately 1.5 fold, compared to LPS-stimulated cells. C. longa showed an anti-inflammatory mechanism of action, reducing IL-8, TNF-α and IL-6 production by approximately 30%, 25% and 40%, respectively, compared to the inflammatory stimuli. B. serrata action was linked to its antioxidant effect, with ROS production being reduced by 25%, compared to H₂O₂-stimulated Caco-2 cells. C. longa and B. serrata resulted to be promising agents for the management of inflammatory bowel diseases by modulating in vitro parameters which have been identified in the clinical conditions.

Background and Aim. Since virus-related hepatocellular carcinoma (HCC) pathogenesis involves liver inflammation, therefore, post-hepatitis C virus (HCV) infection would be a cause for liver cirrhosis that would progress to HCC. Cytotoxic T cells (Tc) are known to be involved in post-HCV complications and HCC pathogenesis. The inhibitory checkpoint Leukocyte-Associated Immunoglobulin-like Receptor-1 (LAIR-1) is expressed on Tc. Therefore, we aimed to determine whether the Tc expression level of LAIR-1 is associated with HCC progression post-HCV and moreover, to evaluate LAIR-1 expression as a non-invasive biomarker for HCC progression in the context of liver cirrhosis post-HCV genotype 4 (G4) in Egyptian patients’ peripheral venous blood liquid biopsy. We studied LAIR-1 expression on Tc related to the progression of liver cirrhosis in a case-controlled study enrolled 64 patients with post-HCV G4-HCC and 37 patients with post-HCV G4-liver cirrhosis. Methods: LAIR-1 expression was analyzed by flow cytometry. Results: LAIR-1 expression on Tc and the percentage of Tc positive for LAIR-1 (LAIR-1+Tc %) were significantly higher in the post-HCV G4-HCC group compared to the post-HCV G4-liver cirrhosis

Escherichia coli is an indicator microorganism in One Health antibiotic resistance surveillance programmes. The purpose of the study was to describe and compare E. coli isolates obtained from pigs and human contacts from a commercial farm in South Africa using conventional methods and whole genome sequencing (WGS). Porcine E. coli isolates were proportionally more resistant phenotypically and harboured a richer diversity of antibiotic resistance genes, as compared to human E. coli isolates. Different pathovars, namely ExPEC (12.43%, 21/169), ETEC (4.14%; 7/169), EPEC (2.96%, 5/169), EAEC (2.96%, 5/169) and STEC (1.18%, 2/169) were detected at low frequencies. Sequence type complex (STc) 10 were the most prevalent (85.51%, 59/169) among human and porcine isolates. Six STcs (STc10, STc86, STc168, STc206, STc278 and STc469) were shared at the human-livestock interface according to multilocus sequence typing (MLST). Core genome MLST and hierarchical clustering (HC) showed that human and porcine isolates were overall genetically diverse, but some clustering at HC2 to HC200 were observed. In conclusion, even though the isolates shared a spatio-temporal relationship, there were still differences in the virulence potential, antibiotic resistance profiles, and cgMLST and HC according to the source of isolation.

In 2021, an operational research study in two tertiary hospitals, Freetown, showed poor hand hygiene compliance. Recommended actions were taken to improve the situation. Between February-April 2023, a cross-sectional study was conducted in the same two hospitals using the WHO Hand Hygiene tool to assess hand hygiene practices and compare hand hygiene compliance with that observed between June-August 2021. In Connaught hospital, overall hand hygiene compliance improved from 51% to 60% (P<0.001), and this applied to both handwash actions with soap and water and alcohol-based-hand-rub: significant improvements were found in all hospital departments and amongst all healthcare worker cadres. In 34 Military Hospital (34MH), overall hand hygiene compliance decreased from 40% to 32% (P<0.001), with significant decreases observed in all departments and amongst nurses and nursing students. The improvements in Connaught Hospital were attributed to more hand hygiene reminders, better handwash infrastructure and more frequent supervision assessments compared with 34MH where interventions were less well applied, possibly due to extensive hospital reconstruction at the time. In conclusion, improved distribution of hand hygiene reminders, better handwash infrastructure and frequent supervision assessments are effective, and need to be strengthened, scaled-up and combined with other innovative ways to promote good hand hygiene practices.

Parasite control strategies such as blanket anthelmintic treatment of all horses in a herd or interval treatment regimen based on egg reappearance remain widely followed practices for the last several decades. These practices have resulted in the fast emergence of resistance in equine strongyles to all major classes of drugs on the market. In this regard, the guidelines set by the American Association of Equine Practitioners advocate evidence-based strongyle control in horses. It recommends targeted treatment of all heavy egg shedders [> 500 eggs per gram (EPG) of feces] while the low shedders (0-200 EPG) are left untreated to maintain susceptible parasite refugia in a herd. As 50-75% of adult horses in a herd are low shedders, preventing them from unnecessary anthelmintic exposure is critical to tackling resistance. There are various fecal egg count (FEC) techniques with many modifications and variations in use, but none is identified as a gold standard and methods comparison studies are lacking. We hypothesized that the diagnostic performance of commonly used quantitation methodologies differs and the FEC methods must be evaluated to determine the gold standard. In this regard, we performed methods comparison studies using polystyrene beads with size and specific gravity comparable to strongyle eggs, as proxy. The linearity of 12 commonly used FEC methodologies (3 techniques with 4 different solutions) was studied using bead standards in the clinically applicable range (63 to 1,000) to determine their suitability for strongyle egg counts. Deming regression analysis identified Mini-FLOTAC with sugar (specific gravity 1.33) as the test with the greatest coefficient of determination. All tests underestimated the true bead count, and we determined a correction factor (CF) for each test to estimate the true count. CF negates the preference for a gold standard test. Finally, we analyzed the validity of CF for 5 tests with R2>0.95 to accurately quantify strongyle eggs from 40 different horses. Overall, this study identified methodologies with the highest diagnostic performance and the limitations to standardizing routine FEC tests to promote uniformity in implementing AAEP parasite control guidelines.

The aim of the studies was to test the hydraulic pressure losses along the length, local pressure losses, absolute and relative roughness values of the pipeline walls made of modern polymer material. The article presents the results of the experimental studies of hydraulic resistance of pipelines from modern polymer materials, the method of theoretical determination of resistance coefficients in the VALTEC ISO 21003 metal polymer pipeline, the classification and method of determining the values of local hydraulic resistance coefficients of T-Junctions are given, the dependence for determining the Darcy λ hydraulic friction coefficient associated with the value of the equivalent hydraulic roughness coefficient of the inner surface of pipes and the Reynolds number. The experimental data of the hydraulic coefficient of friction Darcy λ was compared with the known theoretical relationships of A.D. Altschul, Colbrooke for smooth pipes, Colbrooke and White, an alternative to the Colbrooke-White, Offengenden equation for low-shear pipes and pipes from polymer materials with Reynolds numbers Re>10^4. Dependence of hydraulic coefficient of friction on relative equivalent roughness of pipeline walls and Reynolds number, specific energy loss per one linear meter on total flow rate in system of hydraulically short pipeline is obtained. The empirical dependence of values of coefficients of local resistance ζ=f(Q2/Q3) from a ratio of the divided expenses of Q2/Q3 of the equal-pass T-Junction α=90 the pipeline to a branch up, on pass in the direct T-Junction and division of streams at various internal pipeline diameters of VALTEC.

Electrically conductive adhesives (ECA’s) are used widely to replace or reinforce lead soldering or conductive metal components in electronic packaging applications such as die attachment, solderless interconnections, component repair, display interconnections, and heat dissipation. Their conductive behavior as well as the associated behaviors such as heat conduction and mechanical behavior (strength, rigidity, deformation and viscoelastic behavior, which may be affected by moisture ingression) are affected by adhesive film thickness, volume fraction, size and shape of the conductive filler, as well as uncured base adhesive viscosity, substrate and filler surface treatment and the applied pressure (during bonding and during conduction). The adhesive resistivity decreases precipitously above a characteristic filler volume fraction called the percolation threshold. In general, micron-sized metal fillers mixed in an adhesive (often an epoxy) resulting with different film thicknesses exhibit thickness thresholds for transition from three-dimensional conductivity to two-dimensional conductivity with considerable increases in thickness-direction (z-axis) resistivity when the film thicknesses are smaller than these threshold values. Recently, the use of conductive nanoparticles allowed decreases in percolation threshold levels as well as increases in mechanical strength and durability of ECA’s. Most ECA’s are supplied in liquid or paste form in varying viscosities and therefore, the method of their application also affects their performance. This work intends to provide an understanding of these effects on conduction behavior in (usually high-priced) equipment in which they are used.

Whether the different NR-AMPs could ever be utilized as drugs not only against prokaryotic (bacteria) pathogens but eukaryotic (fungal pathogens, and parasitic protists) depends on the side effects. To get experimental experience about the option of applying EPB-produced antimicrobials to pathogens, and parasites of veterinary significance, we present here the results of an in vitro, and an accompanying in vivo study on chicken. In the in vitro study, we tested the cytotoxic potential of the cell-free conditioned culture media (CFCM) of three entomopathogenic bacterium species, - X. budapestensis, DSM16342 (EMA); X. szentirmaii DSM16338 (EMC); Photorhabdus luminescens ssp. akhurstii TT01 - on chicken tissue culture cells, namely, on the Leghorn Male Hepatoma (LMH), [92] cells, (a permanent confluent hepato-carcinoma cell line). Each CFCM proved rather cytotoxic in this test. In the in vivo study, we fed freshly hatched male broiler chickens for 42 days with XENOFOOD [39] which contained autoclaved cultures of EMA, and EMC). These bacteria were grown on standard chicken (starter and grower) [HM3] [u4] feed, and the whole culture was used as a “food supplement”. [HM5]. It had been known that these EPB species cannot grow that is, not viable) atbody temperature (above 33 C).