A novel inhibitory BAK antibody enables assessment of non-activated BAK in cancer cells.

BAX and BAK are pro-apoptotic members of the BCL2 family that are required to permeabilize the mitochondrial outer membrane. The proteins can adopt a non-activated monomeric conformation, or an activated conformation in which the exposed BH3 domain facilitates binding either to a prosurvival protein or to another activated BAK or BAX protein to promote pore formation. Certain cancer cells are proposed to have high levels of activated BAK sequestered by MCL1 or BCLXL, thus priming these cells to undergo apoptosis in response to BH3 mimetic compounds that target MCL1 or BCLXL. Here we report the first antibody, 14G6, that is specific for the non-activated BAK conformer. A crystal structure of 14G6 Fab bound to BAK revealed a binding site encompassing both the α1 helix and α5-α6 hinge regions of BAK, two sites involved in the unfolding of BAK during its activation. In mitochondrial experiments, 14G6 inhibited BAK unfolding triggered by three diverse BAK activators, supporting crucial roles for both α1 dissociation and separation of the core (α2-α5) and latch (α6-α9) regions in BAK activation. 14G6 bound the majority of BAK in several leukaemia cell lines, and binding decreased following treatment with BH3 mimetics, indicating only minor levels of constitutively activated BAK in those cells. In summary, 14G6 provides a new means of assessing BAK status in response to anti-cancer treatments.

Exploring the Clinical Presentation, Course, and Burden of Disease in Generalized Pustular Psoriasis [Podcast].

Generalized pustular psoriasis (GPP) is the most severe form of pustular psoriasis and affects large areas of the body. GPP is a rare disease, and has a variable presentation; thus, its diagnosis is challenging. The onset of symptoms is rapid, with the appearance of painful skin erythema, followed by the widespread eruption of sterile pustules. Acute GPP (called a flare) is often accompanied by systemic symptoms, including high fever, pain in skin lesions, malaise, and fatigue. Approximately half of GPP flares require hospitalization, with an average inpatient duration of 10-14 days. GPP prevalence estimates range from approximately 2-124 cases per million persons, with a female predominance. The most common age of onset of GPP is 40-60 years, although cases have been described in younger adults and children. GPP affects every aspect of patients' lives and has a high physical and psycho-social impact. Recent research on the interleukin-36 pathway associated with GPP led to the development of a GPP-specific treatment, spesolimab, which was approved by the US FDA in September 2022. This podcast explores the clinical presentation, disease course, and burden of disease in GPP, including differential diagnosis and common triggers of an acute flare.

Microfluidics produced ATRA-loaded PLGA NPs reduced tuberculosis burden in alveolar epithelial cells and enabled high delivered dose under simulated human breathing pattern in 3D printed head models.

Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), is second only to COVID-19 as the top infectious disease killer worldwide. Multi-drug resistant TB (MDR-TB) may arise because of poor patient adherence to medications due to lengthy treatment duration and side effects. Delivering novel host directed therapies (HDT), like all trans retinoic acid (ATRA) may help to improve drug regimens and reduce the incidence of MDR-TB. Local delivery of ATRA to the site of infection leads to higher bioavailability and reduced systemic side effects. ATRA is poorly soluble in water and has a short half-life in plasma. Therefore, it requires a formulation step before it can be administered in vivo. ATRA loaded PLGA nanoparticles suitable for nebulization were manufactured and optimized using a scalable nanomanufacturing microfluidics (MF) mixing approach (MF-ATRA-PLGA NPs). MF-ATRA-PLGA NPs demonstrated a dose dependent inhibition of Mtb growth in TB-infected A549 alveolar epithelial cell model while preserving cell viability. The MF-ATRA-PLGA NPs were nebulized with the Aerogen Solo vibrating mesh nebulizer, with aerosol droplet size characterized using laser diffraction and the estimated delivered dose was determined. The volume median diameter (VMD) of the MF-ATRA-PLGA NPs was 3.00 ± 0.18 µm. The inhaled dose delivered in adult and paediatric 3D printed head models under a simulated normal adult and paediatric breathing pattern was found to be 47.05 ± 3 % and 20.15 ± 3.46 % respectively. These aerosol characteristics of MF-ATRA-PLGA NPs supports its suitability for delivery to the lungs via inhalation. The data generated on the efficacy of an inhalable, scalable and regulatory friendly ATRA-PLGA NPs formulation provides a foundation on which further pre-clinical testing can be built. Overall, the results of this project are promising for future research into ATRA loaded NPs formulations as inhaled host directed therapies for TB.

Short and long-term economic implications of biosimilars.

INTRODUCTION: Biosimilars are gaining popularity due to their ability to offer comparable therapeutic benefits at potentially lower costs. AREAS COVERED: This article analyses studies that compare the cost savings of biosimilars with biologics. It also explores market competition dynamics and the impact of policies in countries. The focus is on the advantages of biosimilars in oncology and rheumatological treatments while considering broader economic implications for the pharmaceutical industry such as market displacement, pricing strategies and their influence on innovation and healthcare sustainability. EXPERT OPINION: The introduction of biosimilars marks a shift in healthcare economics by offering cost reductions and long-term potential for economic balance. However, I also recognize challenges related to research methodologies and regulatory inconsistencies across countries. To fully capitalize on their potential, future research and development in the field of biosimilars must emphasize harmonized approaches and comprehensive studies that ensure both cost containment in healthcare and wider access, to high quality treatments.

Investigation of community pharmacists' knowledge and attitudes of pharmacogenomics testing: implication for improved pharmacogenomic testing practice.

BACKGROUND: Community pharmacists must be well-equipped to advance pharmacogenomics services. Nevertheless, limited data is available regarding pharmacists' knowledge and attitudes toward pharmacogenomics testing. The present study aimed to evaluate community pharmacists' knowledge and attitudes toward pharmacogenomics testing in the UAE. METHODS: In this cross-sectional study, a validated, online, self-administered survey, was randomly distributed to community pharmacists across the United Arab Emirates (UAE). RESULTS: The participants demonstrated poor knowledge about pharmacogenomic testing (median score < 8). Having 10-29 (Adjusted odds ration [AOR]: 0.038; 95% CI: 0.01-0.146, p = 0.001) and 30-49 (AOR: 0.097; 95% CI: 0.04-0.237, p = 0.001) patients per day was associated with poorer knowledge. Also, receiving 10-29 (AOR: 0.046; 95% CI: 0.005-0.401, p = 0.005), 30-49 (AOR: 0.025; 95% CI: 0.003-0.211, p = 0.001), and > 50 (AOR: 0.049; 95% CI: 0.005-0.458, p = 0.008) prescriptions decreased the odds of having good knowledge. Around half (43.9%) of the participants did not show a positive attitude toward pharmacogenomic testing (median score < 11). Having 30-49 patients per day (AOR: 5.351; 95% CI: 2.414-11.860, p = 0.001) increased the odds of good knowledge while receiving 10-29 (AOR: 0.133; 95% CI: 0.056-0.315, p = 0.001) and 30-49 (AOR: 0.111; 95% CI: 0.049-0.252, p = 0.001) prescriptions a day were associated with decreased odds of positive attitude toward the pharmacogenomics testing. CONCLUSIONS: The findings indicate a lack of knowledge and less-than-ideal attitudes among community pharmacists regarding pharmacogenomics testing. Enhanced efforts focused on educational initiatives and training activities related to pharmacogenomics testing is needed. Additionally, reducing workload can facilitate better knowledge acquisition and help mitigate unfavorable attitudes.

Decoding treatment efficacy: uncovering response and failure dynamics to biologics in asthma.

INTRODUCTION: Asthma is a global health problem, with alarming prevalence and mortality rates. Biologic therapies, particularly monoclonal antibodies such as omalizumab, have emerged as promising alternatives, targeting specific immune pathways. This article assesses the efficacy of these biologics in asthma management and attempts to reveal factors associated with their response and failure dynamics. AREA COVERED: This article explores the efficacy of biologics in asthma, biomarkers, and the relationship between asthma phenotypes (including eosinophilic and non-eosinophilic (neutrophilic) types) and biologic treatments; particularly their effectiveness for each subtype. EXPERT OPINION: Personalized asthma management that incorporates molecular insights as well as individual variations is of outmost necessity. An emphasis is put on immunological profiling, understanding comorbidities and considering individual patient factors when managing asthma. Cutting-edge phenotyping tools including omic technologies play a crucial role in improving asthma management precision. Variability in patient responses to biologic treatments such as non-responders, partial responders and super responders poses a formidable challenge to effective asthma care management strategies.