Measurement of adherence to BCR-ABL inhibitor therapy in chronic myeloid leukemia: current situation and future challenges

BCR-ABL inhibitors for treating chronic myeloid leukemia in chronic phase have transformed a previously incurable malignancy into a manageable condition. However, suboptimal medication adherence has been observed with these agents affecting clinical outcomes and healthcare costs. In order to raise awareness of the problem of adherence, and before developing pragmatic strategies to enhance medication adherence, a deep understanding of the best approaches for measuring adherence in chronic myeloid leukemia patients and identifying non-adherence is required. A systematic literature review on the prevalence, measurement methods, consequences and risk factors for non-adherence to BCR-ABL inhibitors and adherence-enhancing interventions was performed and critically appraised. Of the 19 included articles, 9 were retrospective. Average adherence varied from 19% to almost 100% of the proportion of prescribed drug taken, but it was measured through various different methods and within different study groups. Suboptimal adherence was associated with a negative impact on both clinical and economic outcomes. There is a lack of supportive evidence demonstrating a difference in adherence across BCR-ABL inhibitors and even contradictory results between the 2^nd generation inhibitors. Drug-related adverse events and forgetfulness were common reasons for intentional and unintentional non-adherence, respectively, but further research is required to identify additional reasons behind non-adherence or patients at risk of non-adherence. Non-adherence in chronic myeloid leukemia patients treated with BCR-ABL inhibitors is common and associated with critical outcomes. However, this review highlights important existing gaps, reveals inconsistent definitions, and a lack of standardized methods for measuring adherence in chronic myeloid leukemia. All require further investigation.     

The heterogeneous immune microenvironment in breast cancer is affected by hypoxia-related genes

The immune system constitutes an important first-line defence against malignant transformation. However, cancer mediated immunosuppression inactivates the mechanisms of host immune surveillance. Cancer cells shut down anti-cancer immunity through direct cell–cell interactions with leukocytes and through soluble factors, establishing an immunosuppressive environment for unimpeded cancer growth. The composition of the immunosuppressive microenvironment in breast tumours is not well documented. To address this question, selected immunosuppressive factors were analyzed in tumour specimens from 33 breast cancer patients after surgery. The mRNA expression of selected genes was quantified in fresh tumour samples. Tumour infiltrating leukocytes were characterized by flow cytometry to identify regulatory T cells, myeloid derived suppressor cells, and type 2 macrophages. Statistical analysis revealed several interesting correlations between the studied parameters and clinical features. Overall, a surprisingly high degree of heterogeneity in the composition of the immunosuppressive environment was found across all breast cancer samples which adds to the complexity of this disease. The influence of the hypoxia inducible factors (HIFs) on the immune microenvironment was also addressed. The level of HIFs correlated with hormone receptor status and the expression of several immunosuppressive molecules. Targeting HIFs might not only sensitize breast tumours for radiation and chemotherapies but also interfere with cancer immunosuppression.     

A single nucleotide polymorphism −35 kb T > C (rs9264942) is strongly associated with psoriasis vulgaris depending on HLA-Cw06

HLA class I molecules play a role both in viral infection control and in autoimmune diseases development. rs9264942T > C polymorphism in HLA-C gene was found to impact on HLA-C surface expression level and to be associated with HIV-1 control. It was found that these HLA alleles which protect against AIDS are associated with autoimmune disease e.g. psoriasis vulgaris (PsV). Whether rs9264942 SNP is associated with PsV was investigated here. rs9264942T > C was genotyped in 292 PsV patients, and 254 controls using TaqMan Genotyping Assay.     

Fluazuron-induced morphological changes in Rhipicephalus sanguineus Latreille, 1806 (Acari: Ixodidae) nymphs: An ultra-structural evaluation of the cuticle formation and digestive processes

Rhipicephalus sanguineus is a species of tick which is widely distributed in America, Africa and Australia and is probably the most prevalent among all the other ixodid tick species. The present study demonstrated the effects of the arthropod growth regulator fluazuron (Acatak^®), in the formation of the integument and the digestive processes of R. sanguineus nymphs fed on rabbits treated with different doses of this chemical acaricide. For this, three different doses of fluazuron (20 mg/kg, 40 mg/kg and 80 mg/kg) were applied “pour on” to the hosts divided into three different treated-groups (II, III, IV) of three animals each. A fourth group (I) of rabbits (n = 3) was given distilled water as control. On the first day after treatment (24 h), the hosts were artificially infested with R. sanguineus nymphs. After full engorgement (7 days), the nymphs were removed and placed on labeled Petri dishes and kept in BOD incubator for 7 days. The engorged nymphs were then taken to ultra-structural analysis. Results revealed the following main ultra-structural changes in the nymphs integument and midgut of the different treated groups (II, III, IV): cuticle disorganization and the absence of subdivisions, damages in the integument epithelial cells, size of digestive cells, amount of endosomes, autophagic and digestive vacuoles, accumulated digestive residues, lipid droplets and organelles found in the digestive cells’ cytoplasm, as well as the presence of microvilli in their plasma membranes. It is concluded that fluazuron may act on the integument and midgut cells of R. sanguineus engorged nymphs by impairing the synthesis of the new cuticle and the digestive processes (absorption of the blood ingested from the host, digestion – hemolysis, formation of digestive residues and release of nutrients to be converted into lipid, as well as for the synthesis of structural protein), which interfere in the development of nymphs, being able to prevent the emergence of adults after periodical ecdysis. These data indicate the possibility to use this arthropod growth regulator (AGR) in the control of R. sanguineus, at least in the nymphal stage of its biological cycle.     

Synthesis and Potential Applications of Lipid Nanoparticles in Medicine

Currently, carriers of active ingredients in the form of particles of a size measured in nanometers are the focus of interest of research centers worldwide. So far, submicrometer emulsions, liposomes, as well as microspheres, and nanospheres made of biodegradable polymers have been used in medicine. Recent studies show particular interest in nanoparticles based on lipids, and at the present time, are even referred to as the “era of lipid carriers”. With the passage of time, lipid nanoparticles of the so-called first and second generation, SLN (Solid Lipid Nanoparticles) and nanostructured lipid carriers and NLC (Nanostructured Lipid Carriers), respectively, turned out to be an alternative for all imperfections of earlier carriers. These carriers are characterized by a number of beneficial functional properties, including, among others, structure based on lipids well tolerated by the human body, high stability, and ability to carry hydro- and lipophilic compounds. Additionally, these carriers can enhance the distribution of the drug in the target organ and alter the pharmacokinetic properties of the drug carriers to enhance the medical effect and minimize adverse side effects. This work is focused on the current review of the state-of-the-art related to the synthesis and applications of popular nanoparticles in medicine, with a focus on their use, e.g., in COVID-19 vaccines.     

Bioconjugation Strategy for Ceramic Membranes Decorated with Candida Antarctica Lipase B—Impact of Immobilization Process on Material Features

A strategy for the bioconjugation of the enzyme Candida antarctica lipase B onto titania ceramic membranes with varied pore sizes (15, 50, 150, and 300 kDa) was successfully performed. The relationship between the membrane morphology, i.e.,the pore size of the ceramic support, and bioconjugation performance was considered. Owing to the dimension of the enzyme (~33 kDa), the morphology of the ceramics allowed (50, 150, and 300 kDa) or did not allow (15 kDa) the entrance of the enzyme molecules into the porous structure. Such a strategy made it possible to better understand the changes in the material (morphology) and physicochemical features (wettability, adhesiveness, and surface charge) of the samples, which were systematically examined. The silane functionalization and enzyme immobilization were accomplished via the covalent route. The samples were characterized after each stage of the modification, which was very informative from the material point of view. As a consequence of the modification, significant changes in the contact angle, roughness, adhesion, and zeta potential were observed. For instance, for the 50 kDa membrane, the contact angle increased from 29.1 ± 1.5° for the pristine sample to 72.3 ± 1.5° after silane attachment; subsequently, it was reduced to 57.2 ± 1.5° after the enzyme immobilization. Finally, the contact angle of the bioconjugated membrane used in the enzymatic process rose to 92.9 ± 1.5°. By roughness (S_q) controlling, the following amendments were noticed: for the pristine 50 kDa membrane, S_q = 1.87 ± 0.21 µm; after silanization, S_q = 2.33 ± 0.30 µm; after enzyme immobilization, S_q = 2.74 ± 0.26 µm; and eventually, after the enzymatic process, S_q = 2.37 ± 0.27 µm. The adhesion work of the 50 kDa samples was equal to 136.41 ± 2.20 mN m⁻¹ (pristine membrane), 94.93 ± 2.00 mN m⁻¹ (with silane), 112.24 ± 1.90 mN m⁻¹ (with silane and enzyme), and finally, 69.12 ± 1.40 mN m⁻¹ (after the enzymatic process). The materials and physicochemical features changed substantially, particularly after the application of the membrane in the enzymatic process. Moreover, the impact of ceramic material morphology on the zeta potential value is here presented for the first time. With an increase in the ceramic support cut-off, the amount of immobilized lipase rose, but the specific productivity was higher for membranes possessing smaller pores, owing to the higher grafting density. For the enzymatic process, two modes of accomplishment were selected, i.e., stirred-tank and cross-flow. The latter method was characterized by a much higher effectiveness, with a resulting productivity equal to 99.7 and 60.3 µmol h⁻¹ for the 300 and 15 kD membranes, respectively.     

Sarcoidosis of the paranasal sinuses

European Archives of Oto-Rhino-Laryngology - Sarcoidosis is a chronic disease, which predominantly affects the lung. Since sinonasal sarcoidosis is rare, little is known about the sarcoidosis...     

Magnesium as an Important Factor in the Pathogenesis and Treatment of Migraine—From Theory to Practice

So far, no coherent and convincing theory has been developed to fully explain the pathogenesis of migraine, although many researchers and experts emphasize its association with spreading cortical depression, oxidative stress, vascular changes, nervous excitement, neurotransmitter release, and electrolyte disturbances. The contribution of magnesium deficiency to the induction of cortical depression or abnormal glutamatergic neurotransmission is a likely mechanism of the magnesium–migraine relationship. Hence, there is interest in various methods of assessing magnesium ion deficiency and attempts to study the relationship of its intra- and extracellular levels with the induction of migraine attacks. At the same time, many clinicians believe that magnesium supplementation in the right dose and form can be a treatment to prevent migraine attacks, especially in those patients who have identified contraindications to standard medications or their different preferences. However, there are no reliable publications confirming the role of magnesium deficiency in the diet as a factor causing migraine attacks. It also seems interesting to deepen the research on the administration of high doses of magnesium intravenously during migraine attacks. The aim of the study was to discuss the probable mechanisms of correlation of magnesium deficiency with migraine, as well as to present the current clinical proposals for the use of various magnesium preparations in complementary or substitute pharmacotherapy of migraine. The summary of the results of research and clinical observations to date gives hope of finding a trigger for migraine attacks (especially migraine with aura), which may turn out to be easy to diagnose and eliminate with pharmacological and dietary supplementation.     

Response Surface Methodology and Artificial Neural Network Modelling of Membrane Rotating Biological Contactors for Wastewater Treatment

Membrane fouling is a major hindrance to widespread wastewater treatment applications. This study optimizes operating parameters in membrane rotating biological contactors (MRBC) for maximized membrane fouling through Response Surface Methodology (RSM) and an Artificial Neural Network (ANN). MRBC is an integrated system, embracing membrane filtration and conventional rotating biological contactor in one individual bioreactor. The filtration performance was optimized by exploiting the three parameters of disk rotational speed, membrane-to-disk gap, and organic loading rate. The results showed that both the RSM and ANN models were in good agreement with the experimental data and the modelled equation. The overall R² value was 0.9982 for the proposed network using ANN, higher than the RSM value (0.9762). The RSM model demonstrated the optimum operating parameter values of a 44 rpm disk rotational speed, a 1.07 membrane-to-disk gap, and a 10.2 g COD/m² d organic loading rate. The optimization of process parameters can eliminate unnecessary steps and automate steps in the process to save time, reduce errors and avoid duplicate work. This work demonstrates the effective use of statistical modeling to enhance MRBC system performance to obtain a sustainable and energy-efficient treatment process to prevent human health and the environment.