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Successful treatment of glioblastoma multiforme (GBM), an aggressive form of primary brain neoplasm, mandates the need to develop new therapeutic strategies. In this study, we investigated the potential of PBI-05204 in targeting GBM stem cells (GSCs) and the underlying mechanisms. Treatment with PBI-05204 significantly reduced both the number and size of tumor spheres derived from patient-derived GSCs (GBM9, GSC28 and TS543), and suppressed the tumorigenesis of GBM9 xenografts. Moreover, PBI-05204 treatment led to a significant decrease in the expression of CD44 and NANOG, crucial markers of progenitor stem cells, in GBM9 and GSC28 GSCs. This treatment also down-regulated GRP78 expression in both GSC types. Knocking down GRP78 expression through GRP78 siRNA transfection in GBM9 and GSC28 GSCs also resulted in reduced spheroid size and CD44 expression. Combining PBI-05204 with GRP78 siRNA further decreased spheroid numbers compared to GRP78 siRNA treatment alone. PBI-05204 treatment led to increased expression of pRIP1K and pRIP3K, along with enhanced binding of RIPK1/RIPK3 in GBM9 and GSC28 cells, resembling the effects observed in GRP78-silenced GSCs, suggesting that PBI-05204 induced necroptosis in these cells. Furthermore, oleandrin, a principle active cardiac glycoside component of PBI-05204, showed the ability to inhibit the self-renewal capacity in GSCs. These findings highlight the potential of PBI-05204 as a promising candidate for the development of novel therapies that target GBM stem cells., Competing Interests: Declaration of competing interest R. A. Newman and P. Yang are consultants for Phoenix Biotechnology, Inc. The other authors disclosed no potential conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

Background: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with an unpredictable course of recurrent exacerbations alternating with more stable disease. SLE is characterized by broad immune activation and autoantibodies against double-stranded DNA and numerous proteins that exist in cells as aggregates with nucleic acids, such as Ro60, MOV10, and the L1 retrotransposon-encoded ORF1p., Results: Here we report that these 3 proteins are co-expressed and co-localized in a subset of SLE granulocytes and are concentrated in cytosolic dots that also contain DNA: RNA heteroduplexes and the DNA sensor ZBP1, but not cGAS. The DNA: RNA heteroduplexes vanished from the neutrophils when they were treated with a selective inhibitor of the L1 reverse transcriptase. We also report that ORF1p granules escape neutrophils during the extrusion of neutrophil extracellular traps (NETs) and, to a lesser degree, from neutrophils dying by pyroptosis, but not apoptosis., Conclusions: These results bring new insights into the composition of ORF1p granules in SLE neutrophils and may explain, in part, why proteins in these granules become targeted by autoantibodies in this disease., (© 2024. The Author(s).)

Objectives: To illuminate the poorly understood aetiology of SLE by comparing the gene expression profile of SLE neutrophils with that of neutrophils from patients infected by SARS-CoV-2, a disease (COVID-19) with well-defined antigens and a similar type I interferon response., Methods: RNA sequencing of neutrophils from patients with SLE (n=15) and healthy controls (n=12) was analysed for differential gene expression and modulated pathways. The same analyses were performed on a similar neutrophil dataset from patients with SARS-CoV-2 infection (n=30) and healthy controls (n=8). Next, we carried out comparative analyses to identify common and unique transcriptional changes between the two disease contexts, emphasising genes regulated in opposite directions., Results: We identified 372 differentially expressed genes in SLE neutrophils compared with healthy donor neutrophils (≥2 fold, p<0.05), 181 of which were concordant with transcriptional changes in SARS-CoV-2-infected individuals compared with their respective healthy controls. In contrast, 118 genes demonstrated statistically significant alterations exclusive to SLE, including 28 genes that were differentially expressed in opposite directions in the two diseases., Conclusions: The substantial overlap between neutrophil responses in SLE and COVID-19 suggests that the unknown cause of SLE is functionally similar to a viral infection and drives a similar immune activation and type I interferon response. Conversely, the genes regulated in the opposite direction represent responses unique to SLE. These include tyrosylprotein sulfotransferase-1 and nucleic acid deaminases of the APOBEC family, which can catalyse cytosine-to-uridine editing of both RNA and DNA, and other RNA-modifying enzymes., Competing Interests: Competing interests: TM has received consulting fees from Bristol-Myers Squibb, ROME Therapeutics, Cugene, MiroBio and QiLu Biopharma., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Background: Malignant melanoma in-situ, lentigo maligna (MMIS-LM) can be successfully treated with several different surgical techniques; however, the literature is inconsistent in defining them., Objective: To comprehensively define and describe the national guideline recommended surgical techniques used to treat MMIS-LM to help clarify and standardize this terminology to ensure compliance with the guidelines., Methods: A targeted literature review was performed from 1990 to 2022 focusing on articles that discussed the national guideline recommended surgical techniques of wide local excision, Mohs micrographic surgery (MMS), modified Mohs surgery, and staged excision/Slow-Mohs for MMIS-LM, as well as the related methods of tissue processing. National Comprehensive Cancer Network and American Academy of Dermatology guidelines were reviewed to identify how the techniques need to be employed to be compliant with guideline recommendations., Results: We describe the various surgical and tissue processing techniques and discuss advantages and disadvantages of each., Limitations: This paper was styled as a narrative review defining and clarifying terminology and technique and does not investigate these topics more broadly., Conclusion: Understanding the methodology and terminology for these surgical procedures and tissue processing methods is critical so that both general dermatologists and surgeons can employ these techniques effectively for optimal patient care., Competing Interests: Conflicts of interest None disclosed., (Published by Elsevier Inc.)

Objective. To evaluate a process developed to support research by fourth-year student pharmacists enrolled in an advanced pharmacy practice experience at a health system affiliated with a school of pharmacy. Methods. In 2017, clinical, non-tenure track faculty transitioned from facilitating a fourth-year research elective to implementing a new student research process that matches students to research preceptors at the beginning of the academic year and provides training and resources to them throughout the year. This pre-post study evaluated student pharmacist research participation, dissemination, and placement into a residency or job position at the time of graduation, and then compared data for the three years before the new process was implemented to data for the three years after implementation. Results. Thirty-three fourth-year students assigned to the health system graduated from 2015 to 2017, and 31 graduated from 2018 to 2020. The percentage of students in each cohort who completed research projects increased significantly (48.5% vs 87.1%), the number of projects increased significantly (18 vs 35), the number of presentations increased significantly (29 vs 63), and the number of publications increased significantly (9 vs 20). The percentage of research students who pursued postgraduate training increased (68.8% vs 96.3%), as did their rate of placement into training programs (81.8% vs 92.3%). Of those students who did not participate in research, the percent who pursued training also increased (17.6% vs 75%), but the rate of placement remained the same (66.7%). Conclusion. Matching fourth-year student pharmacists to research preceptors at the beginning of the academic year and providing them with training and resources throughout the year was associated with increased research productivity., (© 2022 American Association of Colleges of Pharmacy.)

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer related death in western countries. The successful treatment of PDAC remains limited. We investigated the effect of Fraction B, which is a fraction purified from catfish ( Arius bilineatus, Val. ) skin secretions containing proteins and lipids, on PDAC biology both in-vivo and in-vitro . We report here that Fraction B potently suppressed the proliferation of both human and mouse pancreatic cancer cells in vitro and significantly reduced the growth of their relevant xenograft (Panc02) and orthotopic tumors (human Panc-1 cells) ( p < 0.05). The Reverse Phase Protein Array (RPPA) data obtained from the tumor tissues derived from orthotopic tumor bearing mice treated with Fraction B showed that Fraction B altered the cancer stem cells related pathways and regulated glucose and glutamine metabolism. The down-regulation of the cancer stem cell marker CD44 expression was further confirmed in Panc-1 cells. CBC and blood chemistry analyses showed no systemic toxicity in Fraction B treated Panc-1 tumor bearing mice compared to that of control group. Our data support that Fraction B is a potential candidate for PDAC treatment., Competing Interests: JA-H carries a number of patents to the use of products from the skin secretion of the catfish. PY shares one of the patents with JA-H on the use of a preparation from the catfish skin secretions. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Al-Hassan, Wei, Chakraborty, Conway, Rhea, Wei, Tran, Gagea, Afzal, Oommen, Nair, Paul and Yang.)

Background: Australia possesses a highly multicultural demographic, and thus dental practitioners are likely to regularly encounter culturally and linguistically diverse individuals. It is important for dental practitioners to be culturally competent, however, cultural competency education is highly variable in the curricula of dentistry and oral health courses in Australia, and research is largely limited to dentistry students. This study aims to investigate and compare perceived attitudes, beliefs and practices of cultural competence amongst first and final year Doctor of Dental Surgery (DDS) and Bachelor of Oral Health (BOH) students at the University of Melbourne Dental School., Methods: Following ethics approval, anonymous questionnaires were completed by 213 participants. The questionnaire was adapted from Schwarz's Healthcare Provider Cultural Competence Instrument and consisted of five scales. Data was analysed using SPSS V 24.0 software., Results: A total of 213 students participated in this study (response rate = 88%) The majority of participants were female (n = 114, 53.5%) and the mean age of 23.5 years (range 18-40). The majority of participants were Australian born (n = 110) with 74.6% (n = 159) first generation Australians. Participants who identified as Australian represented 35.7% (n = 76) with 66.1% (n = 141) identified as partly Australian. Multivariate analysis indicated that, after controlling for other independent variables in the model, those who had the highest cultural competence score were female, who self-identify as "Australian", who were in the final year. Furthermore, those who were in the final BOH year scored significatively higher than final year DDS students., Conclusion: The findings of this study suggest that there is a significant difference in students self-reported cultural competence at different stages of their education. This may be attributed to differences in cultural competence education, scope of practice and the type of patient encounters and role modelling that students may experience. Future research should involve follow up to create longitudinal data, as well as research at other dental schools in Australia and overseas.

Trichomoniasis in humans, caused by the protozoal parasite Trichomonas vaginalis, is the most common non-viral sexually transmitted disease, while Tritrichomonas foetus causes trichomonosis, an infection of the gastrointestinal tract and diarrhea in farm animals and domesticated cats. As part of an effort to determine the inhibitory effects of plant-based extracts and pure compounds, seven commercially available cherry tomato varieties were hand-peeled, freeze-dried, and pounded into powders. The anti-trichomonad inhibitory activities of these peel powders at 0.02% concentration determined using an in vitro cell assay varied widely from 0.0% to 66.7% against T. vaginalis G3 (human); from 0.9% to 66.8% for T. foetus C1 (feline); and from 0.0% to 81.3% for T. foetus D1 (bovine). The organic Solanum lycopersicum var. cerasiforme (D) peels were the most active against all three trichomonads, inhibiting 52.2% (G3), 66.8% (C1), and 81.3% (D1). Additional assays showed that none of the powders inhibited the growth of foodborne pathogenic bacteria, pathogenic fungi, or non-pathogenic lactobacilli. Tomato peel and pomace powders with high content of described biologically active compounds could serve as functional food and feed additives that might help overcome adverse effects of wide-ranging diseases and complement the treatment of parasites with the anti-trichomonad drug metronidazole.

Background: Incentive spirometers were developed to facilitate sustained maximum inspiration. In addition to a slow-rising float that indicates volume displacement, the incentive spirometers includes a sensitive, rapid-fluttering flow indicator. Achieving the target inspiratory volume is believed to be the most important factor in successful incentive spirometers use. This investigation hypothesized that patients focus on the rapid fluttering of the flow indicator rather than volume float during incentive spirometers use. The effects of adjusting hand positioning to cover the flow indicator on inspiratory volumes were evaluated., Methods: A randomized, prospective, counter-balanced crossover analysis of postoperative subjects was completed. In alternating assignment, the subjects were randomized to 1 of 2 study groups: (A) with the flow indicator covered first followed by the flow indicator standard exposed, and (B) with the flow indicator standard exposed first, followed by the flow indicator covered. The subjects were asked to perform 2 inhalations on their incentive spirometers in the first flow indicator condition: covered or the standard exposed. After a 2-min delay, the subjects were then asked to perform an additional 2 inhalations with the alternate flow indicator condition. The difference between mean inspiratory volumes under covered and standard exposed conditions was evaluated for all subjects, within and between groups., Results: A total of 42 subjects were evaluated. For all the subjects, there was a mean increase of 255.4 mL of inspired volume when the flow indicator was covered (1,869.0 vs 1,613.7 mL, P < .001). For the subjects in group B who had their flow indicators covered after standard exposure, mean inspiratory volumes increased by 285.7 mL (1,613.1 vs 1,898.8 mL, P = .009). For subjects in group A who had their flow indicator covered before standard exposure, their mean inspiratory volumes increased by 225.0 mL (1,614.3 vs 1839.3 mL, P = .007) when covered. There was no significant difference between the mean increases across patients in groups A and B (225.0 vs 285.7 mL, P = .63)., Conclusions: Covering the flow indicator during incentive spirometers significantly increased achieved inspiratory volumes. Increased volumes were generated, irrespective of flow indicator covering order, which strongly suggested that the covering effect was greater than any learning or condition order carry-over effects. Because achieving target inspiratory volumes is considered the most important factor in successful incentive spirometers use, these findings may have immediate applications for improving incentive spirometers protocols, patient education, and device design implications., (Copyright © 2019 by Daedalus Enterprises.)

Background: Incentive spirometers (IS) are commonly prescribed after various surgical procedures with the intended effect of reducing postoperative pulmonary complications. Factors associated with correct use of IS by postoperative patients has not previously been studied., Methods: A cross-sectional analysis of postoperative patients was completed to assess whether patients knew how to correctly inhale on their IS. For each patient, the following variables were collected: whether the device was within arm's reach of the patient, if the patient reported having used their IS, if they considered the IS to be helpful, and if they felt more confident using IS after a brief educational intervention was performed by study investigators., Results: A total of 26.2% (11/42) of patients failed to use their IS correctly, and 38.1% (16/42) denied ever using the device in their postoperative care. Device location, perceived benefit, and previous use were identified as statistically significant determinants of successful use. Following a brief educational intervention by a physician, 73.8% (31/42) of patients were more confident in their ability to use IS during the remainder of their care., Discussion: A substantial portion of postoperative patients failed to correctly utilize their IS. Device proximity to the patient, patient perspectives on potential benefits of IS, and previous use of the device may affect correct use. Patient education and optimization of device placement should be considered to increase compliance during IS implementation.

On the basis of the previously reported clinical candidate, SSA-426 (1), a series of related 2-piperazin-1-ylquinoline derivatives 3-16 were synthesized and evaluated as dual-acting serotonin (5-HT) reuptake inhibitors and 5-HT1A receptor antagonists. In particular, compound 7 exhibits potent functional activities at both the 5-HT transporter and 5-HT1A receptor, good selectivity over the alpha1-adrenergic and dopaminergic receptors, acceptable pharmacokinetic properties, and a favorable in vivo profile.

2,3-Dihydro-1,4-benzodioxanes with aryl 8-aza-bicyclo[3.2.1]oct-3-ene attachments 2 produce compounds with potent 5-HT-T affinity, and weak 5-HT(1A) affinity and alpha(1) affinity. This compares with 2,3-dihydro-1,4-benzodioxanes containing 8-aza-bicyclo[3.2.1] octan-3-ol attachments 4 which possess potent 5-HT(1A) affinity, moderate to good selectivity over alpha(1) and little 5-HT-T affinity. A 3-benzothiophene analogue of 4 (30) was synthesized which possesses potent 5-HT(1A) affinity and especially good selectivity over both alpha(1) and 5-HT-T.