Development and characterization of a temozolomide-loaded nanoemulsion and the effect of ferrocene pre and co-treatments in glioblastoma cell models.

BACKGROUND: Glioblastoma is a severe brain tumor that requires aggressive treatment involving surgery, radiotherapy, and chemotherapy, offering a survival rate of only 15 months. Fortunately, recent nanotechnology progress has enabled novel approaches and, alongside ferrocenes' unique properties of cytotoxicity, sensitization, and interaction with reactive oxygen species, have brought new possibilities to complement chemotherapy in nanocarrier systems, enhancing treatment results. METHODS: In this work, we developed and characterized a temozolomide-loaded nanoemulsion and evaluated its cytotoxic potential in combination with ferrocene in the temozolomide-resistant T98G and temozolomide-sensitive U87 cell lines. The effects of the treatments were assessed through acute assays of cell viability, cell death, mitochondrial alterations, and a treatment protocol simulation based on different two-cycle regimens. RESULTS: Temozolomide nanoemulsion showed a z-average diameter of 173.37 ± 0.86 nm and a zeta potential of - 6.53 ± 1.13 mV. Physicochemical characterization revealed that temozolomide is probably associated with nanoemulsion droplets instead of being entrapped within the nanostructure, allowing a rapid drug release. In combination with ferrocene, temozolomide nanoemulsion reduced glioblastoma cell viability in both acute and two-cycle regimen assays. The combined treatment approach also reversed T98G's temozolomide-resistant profile by altering the mitochondrial membrane potential of the cells, thus increasing reactive oxygen species generation, and ultimately inducing cell death. CONCLUSIONS: Altogether, our results indicate that using nanoemulsion containing temozolomide in combination with ferrocene is an effective approach to improve glioblastoma therapy outcomes.

Design, development and in vitro quantification of novel electrosprayed everolimus-loaded Soluplus®/Polyvinyl alcohol nanoparticles via stability-indicating HPLC method in cancer therapy.

Everolimus (RAD001) a mammalian target of rapamycin has been hampered by poor solubility, affecting its dissolution rate, a relationship that extends to low bioavailability. Nanoparticles (NP) based on Soluplus (SOL®) and Polyvinyl alcohol (PVA) was fabricated by electrospraying (ES) for the delivery of RAD001 to improve anti-tumour efficacy. Electrospraying with established experimental conditions produced PVA-SOL®-RAD001 NP with 71 nm mean diameter, smaller particle size distribution and >90 % encapsulation efficiency. Various polymer-drug concentrations exposed to various freeze-thaw (F/T) cycles were studied for NP optimisation and to enhance its mechanical properties. The optimised NP formulation demonstrated complete encapsulation as well as a sustained and pH dependent drug release profile for in vitro release test. In addition, to specifically study the degradation profile of RAD001 and to quantify RAD001 in the fabricated NP, a new HPLC method was developed and validated. The purpose and novelty of the HPLC method was also to ensure that RAD001 can be detected at low amounts where other conventional characterisation methods are unable to detect. The developed HPLC method was accurate, precise, robust and sensitive with LOD and LOQ values of 4.149 and 12.575 µg/mL. In conclusion, the novel developed HPLC system can be applied for the quantification of different chemotherapeutic agents and the novel electrosprayed hydrogel NP is a potential drug delivery system to increase solubility and bioavailability of RAD001 in cancer therapy.

ACTivity as medicine In Oncology for Head and Neck (ACTIOHN): Protocol for a feasibility study investigating a patient-centred approach to exercise for people with head and neck cancer.

BACKGROUND AND AIM: Attempts at personalisation of exercise programmes in head and neck cancer (HaNC) have been limited. The main aim of the present study is to investigate the feasibility and acceptability of introducing a remotely delivered, fully personalised, collaborative, and flexible approach to prescribing and delivering exercise programmes into the HaNC usual care pathway. METHODS: This is a single arm, feasibility study. Seventy patients diagnosed with HaNC will be recruited from two regional HaNC centres in the United Kingdom. Patients will undertake an 8-week exercise programme designed and delivered by cancer exercise specialists. The exercise programme will start any time between the time of diagnosis and up to 8 weeks after completing treatment, depending on patient preference. The content of the exercise programme will be primarily based on patient needs, preferences, and goals, but guided by current physical activity guidelines for people with cancer. The primary outcome measure is retention to the study. Secondary quantitative outcomes are uptake to the exercise programme, different measures of exercise adherence, pre- and post-intervention assessments of fatigue (Multidimensional Fatigue Symptom Inventory-Short Form), quality of life (SF-36), physical activity levels (International Physical Activity Questionnaire-Short Form), and various components of physical fitness. The outcomes of the nested qualitative study are acceptability and feasibility of the intervention evaluated via interviews with patients, health care professionals, and the cancer exercise specialists. Intervention and participant fidelity will be determined using checklists and scrutiny of each patient's logbook and the cancer exercise specialists' meeting notes. Analysis of quantitative data will be via standard summary statistics. Qualitative data will be analysed using thematic analysis. EXPECTED RESULTS: This feasibility study will inform the design and conduct of a future randomised controlled trial. Success will be defined according to a traffic light system for identifying the appropriateness of progression to a randomised controlled trial. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number registry (ISRCTN82505455).

Nanofibrillated cellulose originated from Rhododendron ponticum to produce scaffolds using 3D printing for biomedical applications.

Rhododendron ponticum is an invasive species that spreads rapidly and is described as one of the biggest threats to peatlands in Ireland. This study offers an innovative approach to utilizing Rhododendron waste. Initially, sawdust was submitted to a bleaching treatment and the nanofibrillated cellulose (NFC) was obtained using two different methods: ultra-fine friction grinding and twin-screw extrusion with the assistance of TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) pre-treatment. The samples processed through twin-screw extrusion exhibited the presence of NFC at five intervals, as confirmed by TEM analysis. However, these samples displayed a higher diameter deviation compared to those processed through grinding alone. Notably, after 20 extrusion steps, the NFC diameter became more uniform, reaching approximately 35 nm. Sedimentation tests showed that extrusion produced more homogeneous cellulose size than the grinder method. However, FTIR characterization for the samples showed a unique band related to C-O-C glycosidic linkage. The results showed that grinding breaks these groups resulting in crystallinity values lower than extrusion, 50 % compared 60 %. Therefore, NFC with 20 steps by grinding was blended with polycaprolactone to produce a 3D scaffold using a 3D printer at different ratios of 1-5 % addition. The effect of 1 % of NFC was unique showing significant enhanced mechanical properties compared to pure polycaprolactone (PCL), additionally, the NFC does not exhibit toxicity so these materials show promise for biomedical applications.

Is the early identification and referral of suspected head and neck cancers by community pharmacists feasible? A qualitative interview study exploring the views of patients in North East England.

INTRODUCTION: Head and neck cancer (HNC) is the eighth most common cancer in the United Kingdom. Survival rates improve when the cancer is diagnosed at an early stage, highlighting a key need to identify at-risk patients. This study aimed to explore opportunistic HNC identification and referral by community pharmacists (CPs) using a symptom-based risk assessment calculator, from the perspective of patients with a diagnosis of HNC. METHODS: Purposive sampling was used to recruit patients from the HNC pathway in three large teaching hospitals in Northern England. Qualitative methodology was used to collect data through an iterative series of semistructured telephone interviews. Framework analysis was utilised to identify key themes. RESULTS: Four main themes were constructed through the analytic process: (1) HNC presentation and seeking help; (2) the role of the CP; (3) public perception of HNC and (4) the role of a symptom-based risk calculator. Participants agreed that CPs could play a role in the identification and referral of suspected HNCs, but there were concerns about access as patients frequently only encounter the medicine counter assistant when they visit the pharmacy. HNC symptoms are frequently attributed to common or minor conditions initially and therefore considered not urgent, leading to delays in seeking help. While there is public promotion for some cancers, there is little known about HNC. Early presentation of HNC can be quite variable, therefore raising awareness would help. The use of a symptom-based risk calculator was considered beneficial if it enabled earlier referral and diagnosis. Participants suggested that it would also be useful if the public were made aware of it and could self-assess their symptoms. CONCLUSION: In principle, CPs could play a role in the identification and referral of HNC, but there was uncertainty as to how the intervention would work. Future research is needed to develop an intervention that would facilitate earlier identification and referral of HNC while not disrupting CP work and that would promote HNC and the risk calculator more widely. PATIENT OR PUBLIC CONTRIBUTION: Patient and public involvement and engagement (PPIE) was integrated throughout the project. Initially, the proposal was discussed during a Cancer Head and Neck Group Experience (CHANGE) PPIE meeting. CHANGE was set up to support HNC research in 2018. The group is composed of seven members (four female, three male) with an age range of 50-71 years, who were diagnosed at Sunderland Royal Hospital. A patient representative from the University of Sunderland PPIE group and a trustee of the Northern HNC Charity were recruited as co-applicants. They attended project management group meetings and reviewed patient-facing documentation.

Electrospun Drug-Loaded and Gene-Loaded Nanofibres: The Holy Grail of Glioblastoma Therapy?

To date, GBM remains highly resistant to therapies that have shown promising effects in other cancers. Therefore, the goal is to take down the shield that these tumours are using to protect themselves and proliferate unchecked, regardless of the advent of diverse therapies. To overcome the limitations of conventional therapy, the use of electrospun nanofibres encapsulated with either a drug or gene has been extensively researched. The aim of this intelligent biomaterial is to achieve a timely release of encapsulated therapy to exert the maximal therapeutic effect simultaneously eliminating dose-limiting toxicities and activating the innate immune response to prevent tumour recurrence. This review article is focused on the developing field of electrospinning and aims to describe the different types of electrospinning techniques in biomedical applications. Each technique describes how not all drugs or genes can be electrospun with any method; their physico-chemical properties, site of action, polymer characteristics and the desired drug or gene release rate determine the strategy used. Finally, we discuss the challenges and future perspectives associated with GBM therapy.

Sexual Dimorphism in the Closure of the Hippocampal Postnatal Critical Period of Synaptic Plasticity after Intrauterine Growth Restriction: Link to Oligodendrocyte and Glial Dysregulation.

Intrauterine growth restriction (IUGR) resulting from hypertensive disease of pregnancy (HDP) leads to sexually dimorphic hippocampal-dependent cognitive and memory impairment in humans. In our translationally relevant mouse model of IUGR incited by HDP, we have previously shown that the synaptic development in the dorsal hippocampus including GABAergic development, NPTX2+ excitatory synaptic formation, axonal myelination, and perineural net (PNN) formation were perturbed by IUGR at adolescent equivalence in humans (P40). The persistence of these disturbances through early adulthood and the potential upstream mechanisms are currently unknown. Thus, we hypothesized that NPTX2+ expression, PNN formation, axonal myelination, all events closing synaptic development in the hippocampus, will be persistently perturbed, particularly affecting IUGR female mice through P60 given the fact that they had worse short-term recognition memory in this model. We additionally hypothesized that such sexual dimorphism is linked to persistent glial dysregulation. We induced IUGR by a micro-osmotic pump infusion of a potent vasoconstrictor U-46619, a thromboxane A2-analog, in the last week of the C57BL/6 mouse gestation to precipitate HDP. Sham-operated mice were used as controls. At P60, we assessed hippocampal and hemispheric volumes, NPTX2 expression, PNN formation, as well as myelin basic protein (MBP), Olig2, APC/CC1, and M-NF expression. We also evaluated P60 astrocytic (GFAP) reactivity and microglial (Iba1 and TMEM119) activation using immunofluorescent-immunohistochemistry and Imaris morphological analysis plus cytokine profiling using Meso Scale Discovery platform. IUGR offspring continued to have smaller hippocampal volumes at P60 not related to changes in hemisphere volume. NPTX2+ puncta counts and volumes were decreased in IUGR hippocampal CA subregions of female mice compared to sex-matched shams. Intriguingly, NPTX2+ counts and volumes were concurrently increased in the dentate gyrus (DG) subregion. PNN volumes were smaller in CA1 and CA3 of IUGR female mice along with PNN intensity in CA3 but they had larger volumes in the CA3 of IUGR male mice. The myelinated axon (MBP+) areas, volumes, and lengths were all decreased in the CA1 of IUGR female mice compared to sex-matched shams, which correlated with a decrease in Olig2 nuclear expression. No decrease in the number of APC/CC1+ mature oligodendrocytes was identified. We noted an increase in M-NF expression in the mossy fibers connecting DG to CA3 only in IUGR female mice. Reactive astrocytes denoted by GFAP areas, volumes, lengths, and numbers of branching were increased in IUGR female CA1 but not in IUGR male CA3 compared to sex-matched shams. Lastly, activated microglia were only detected in IUGR female CA1 and CA3 subregions. We detected no difference in the cytokine profile between sham and IUGR adult mice of either sex. Collectively, our data support a sexually dimorphic impaired closure of postnatal critical period of synaptic plasticity in the hippocampus of young adult IUGR mice with greater effects on females. A potential mechanism supporting such dimorphism may include oligodendrocyte dysfunction in IUGR females limiting myelination, allowing axonal overgrowth followed by a reactive glial-mediated synaptic pruning.

Qualitative interview study exploring the early identification and referral of patients with suspected head and neck cancer by community pharmacists in England.

OBJECTIVE: To explore pharmacists' perceptions of, and attitudes towards, the early identification and referral of patients with signs and symptoms indicating potential diagnosis of head and neck cancer (HNC) in community pharmacy settings. DESIGN: Qualitative methodology, using constant comparative analysis to undertake an iterative series of semistructured interviews. Framework analysis facilitated the identification of salient themes. SETTING: Community pharmacies in Northern England. PARTICIPANTS: 17 community pharmacists. RESULTS: Four salient and inter-related categories emerged: (1) Opportunity and access, indicating frequent consultations with patients presenting with potential HNC symptoms and the accessible nature of community pharmacists; (2) Knowledge gap, indicating knowledge of key referral criteria, but limited experience and expertise in undertaking more holistic patient assessments to inform clinical decision making; (3) Referral pathways and workloads; indicating good working relationships with general medical practices, but limited collaboration with dental services, and a desire to engage with formal referral pathways, but current practices based entirely on signposting resulting in a potential lack of safety-netting, no auditable trail, feedback mechanism or integration into the multidisciplinary team; (4) Utilisation of clinical decision support tools; indicating that no participants were aware the Head and Neck Cancer Risk Calculator (HaNC-RC V2) for HNC but were positive towards the use of such tools to improve decision making. HaNC-RC V2 was seen as a potential tool to facilitate a more holistic approach to assessing patient's symptoms, acting as a prompt to further explore a patient's presentation, requiring further investigation in this context. CONCLUSIONS: Community pharmacies offer access to patients and high-risk populations that could support HNC awareness initiatives, earlier identification and referral. However, further work to develop a sustainable and cost-effective approach to integrating pharmacists into cancer referral pathways is needed, alongside appropriate training for pharmacists to successfully deliver optimum patient care.

Utility of preoperative colour flow Doppler assessment of perforator anatomy in medial sural artery perforator (MSAP) free flaps.

PURPOSE: It is known that the vascular perforators upon which the medial sural artery perforator (MSAP) flap is based are subject to considerable variation. This study seeks to evaluate the use of colour flow Doppler (CFD) as an imaging technique to establish the presence of suitable vessels, the discriminatory findings from that imaging, the rate of flap abandonment and flap complications. METHODS: All patients undergoing MSAP in our institution since 2015 had a pre-operative CFD using a standardised technique. A prior group of 22 patients not having CFD acted as a control group. Data were  collected prospectively. RESULTS: Fourteen patients had CFD. In one patient, no suitable vessels were found. In 13 patients, vessels of suitable size and position were identified, which then correlated precisely with operative findings. Three had suitable vessels in one leg only. No flaps in the CFD group were abandoned. One flap in the CFD group was partially lost. One flap in the prior control group was abandoned. CONCLUSIONS: CFD provided reliable discriminatory information to decide on flap suitability/which leg and correlated precisely with operative findings, with no flap abandonment. Flap survival rate was very high.

Photobiomodulation in the management of oral mucositis for adult head and neck cancer patients receiving irradiation: the LiTEFORM RCT.

BACKGROUND: Oral mucositis is a debilitating and painful complication of head and neck cancer irradiation that is characterised by inflammation of the mucous membranes, erythema and ulceration. Oral mucositis affects 6000 head and neck cancer patients per year in England and Wales. Current treatments have not proven to be effective. International studies suggest that low-level laser therapy may be an effective treatment. OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of low-level laser therapy in the management of oral mucositis in head and neck cancer irradiation. To identify barriers to and facilitators of implementing low-level laser therapy in routine care. DESIGN: Placebo-controlled, individually randomised, multicentre Phase III superiority trial, with an internal pilot and health economic and qualitative process evaluations. The participants, outcome assessors and therapists were blinded. SETTING: Nine NHS head and neck cancer sites in England and Wales. PARTICIPANTS: A total of 87 out of 380 participants were recruited who were aged ≥ 18 years and were undergoing head and neck cancer irradiation with ≥ 60 Gy. INTERVENTION: Random allocation (1 : 1 ratio) to either low-level laser therapy or sham low-level laser therapy three times per week for the duration of irradiation. The diode laser had the following specifications: wavelength 660 nm, power output 75 mW, beam area 1.5 cm2, irradiance 50 mW/cm2, exposure time 60 seconds and fluence 3 J/cm2. There were 20-30 spots per session. Sham low-level laser therapy was delivered in an identical manner. MAIN OUTCOME MEASURE: The mean Oral Mucositis Weekly Questionnaire-Head and Neck Cancer score at 6 weeks following the start of irradiation. Higher scores indicate a worse outcome. RESULTS: A total of 231 patients were screened and, of these, 87 were randomised (low-level laser therapy arm, n = 44; sham arm, n = 43). The mean age was 59.4 years (standard deviation 8.8 years) and 69 participants (79%) were male. The mean Oral Mucositis Weekly Questionnaire-Head and Neck Cancer score at 6 weeks was 33.2 (standard deviation 10) in the low-level laser therapy arm and 27.4 (standard deviation 13.8) in the sham arm. LIMITATIONS: The trial lacked statistical power because it did not meet the recruitment target. Staff and patients willingly participated in the trial and worked hard to make the LiTEFORM trial succeed. However, the task of introducing, embedding and sustaining new low-level laser therapy services into a complex care pathway proved challenging. Sites could deliver low-level laser therapy to only a small number of patients at a time. The administration of low-level laser therapy was viewed as straightforward, but also time-consuming and sometimes uncomfortable for both patients and staff, particularly those staff who were not used to working in a patient's mouth. CONCLUSIONS: This trial had a robust design but lacked power to be definitive. Low-level laser therapy is relatively inexpensive. In contrast with previous trials, some patients found low-level laser therapy sessions to be difficult. The duration of low-level laser therapy sessions is, therefore, an important consideration. Clinicians experienced in oral cavity work most readily adapt to delivering low-level laser therapy, although other allied health professionals can be trained. Blinding the clinicians delivering low-level laser therapy is feasible. There are important human resource, real estate and logistical considerations for those setting up low-level laser therapy services. FUTURE WORK: Further well-designed randomised controlled trials investigating low-level laser therapy in head and neck cancer irradiation are needed, with similar powered recruitment targets but addressing the recruitment challenges and logistical findings from this research. TRIAL REGISTRATION: This trial is registered as ISRCTN14224600. FUNDING: This project was funded by the National Institute for Health and Care Research ( NIHR ) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 46. See the NIHR Journals Library website for further project information.

Around 9 out of 10 head and neck cancer patients undergoing treatment experience pain, swelling and sores in their mouth (oral mucositis). This can lead to weight loss, painful ulcers, difficulty talking, eating and drinking, and even hospitalisation. Current care includes helping patients to keep their mouth and teeth clean, encouraging them to have a healthy diet and prescribing mouthwashes, painkillers and mouth-coating gels. However, these treatments give limited help in preventing or treating this condition. The LiTEFORM trial looked at whether or not low-level laser therapy could be used to prevent and treat oral mucositis. Patients were allocated to one of two arms at random: active laser or fake (sham) laser. Neither the patients nor the hospital staff knew which laser was being used. Eighty-seven people joined the study during the time allowed (44 received low-level laser therapy and 43 received sham treatment); however, this was a smaller number than the planned target of 380 people. As a result, no meaningful conclusion can be drawn from the results about whether the therapy is beneficial or cost-effective. People receiving the low-level laser therapy reported slightly more soreness in their mouth than those receiving the sham laser, but this could be down to chance. The number of participants is too small to draw conclusions about whether or not the low-level laser is helpful. Some patients found the laser treatment sessions to be difficult. Setting up a new service delivering laser therapy at the same time as cancer treatments was more complicated than originally anticipated. Problems included the scheduling of appointments, finding suitable rooms and having enough trained staff with time to deliver laser therapy. However, this study has provided us with knowledge on how best to set up a laser therapy service in the NHS as part of the cancer treatment pathway and the costs involved. These findings could help future studies looking into low-level laser therapy for those with head and neck cancer.

Factors determining postoperative length of stay and time to resumption of feeding following free flap reconstruction for oral cancer.

Microvascular free tissue transfer reconstruction following resection of oral cancer is commonly chosen as the first line of treatment due to its superior functional outcomes. Multiple patient and surgical factors impact the length of postoperative stay, and the time taken for patients to recommence oral feeding. This study aimed to identify factors that increase the length of stay and time to resumption of feeding. We retrospectively evaluated 100 cases from March 2015 to October 2020, and identified variables associated with increased length of stay (LOS) and time to resumption of feeding in univariate and multivariate analyses. Factors found to be associated with increased LOS in multivariate analysis were increasing age, elective tracheostomy, tumours originating from the floor of the mouth and mandible, a longer operating time, and use of fibular free flaps (p<0.05). Tracheostomy, increasing age, and female gender were strongly associated with delays in resumption of some types of oral feeding, and an integrated critical care unit (ICCU) stay of two or more days was associated with a longer time to resumption of free fluids. This information can be used to anticipate extensions to typical LOS, to produce cost analyses, develop individual patient risk stratification, manage patient expectations, and target the use of enhanced recovery programmes.

Characterization of Gels and Films Produced from Pinhão Seed Coat Nanocellulose as a Potential Use for Wound Healing Dressings and Screening of Its Compounds towards Antitumour Effects.

The reuse of agro-industrial waste assumes great importance today. Pinhão is the seed of Araucaria angustifolia, which is native to the mountains of southern Brazil, Paraguay, and Argentina. The coat is a by-product of this seed and is rich in phenolic compounds. The present study aimed to use the residue as a precursor material for the production of nanocellulose through the mechanical defibrillation process and perform the characterization of the films and the gel to investigate the effect on the physical and regenerative properties when incorporated with polyvinyl alcohol (PVA). The modulus of elasticity was higher when the MFC of pinhão was added to the PVA. Film and gel had their cytotoxicity tested by MTT assay using 3T3 fibroblast and Schwann cancer cells, and a migration assay was also performed using the scratch test on HaCat keratinocyte cells. For the scratch test, film and gel samples with low concentration presented a complete scratch closure in 72 h. Molecular docking was performed and quercetin had the ideal interaction score values, so it was used with the PACAP protein which presented a slightly moderate interaction with the protein synthesis of Schwann cells, presenting compactness of the compound after 14 ns.

Self-Photopolymerizable Hydrogel-Ceramic Composites with Scavenger Properties.

The photocatalytic behaviours of semiconductive ceramic nanoparticles such as TiO2, ZnO, Fe2O3, and Fe3O4, have been extensively studied in photocatalysis and photopolymerization, due to their ability to produce radical species under ultraviolet-visible light, and even in dark conditions. In addition, in the form of microparticles, TiO2 and its Magnéli phases are capable of neutralizing radical species, and a heterogeneous catalytic process has been suggested to explain this property, as it is well known as scavenging activity. Thus, in this study, we demonstrate that these ceramic powders, in the form of microparticles, could be used as photoinitiators in UV polymerization in order to synthesize a hydrogel matrix. Them, embedded ceramic powders could be able to neutralize radical species of physiological media once implanted. The hydrogel matrix would regulate the exchange of free radicals in any media, while the ceramic particles would neutralize the reactive species. Therefore, in this work, the scavenger activities of TiO2, ZnO, Fe2O3, and Fe3O4 microparticles, along with their photoinitiation yield, were evaluated. After photopolymerization, the gel fraction and swelling behaviour were evaluated for each hydrogel produced with different ceramic initiators. Gel fractions were higher than 60%, exhibiting variation in their scavenging activity. Therefore, we demonstrate that ceramic photoinitiators of TiO2, ZnO, Fe2O3, and Fe3O4 can be used to fabricate implantable devices with scavenger properties in order to neutralize radical species involved in inflammatory processes and degenerative diseases.

Nek1-inhibitor and temozolomide-loaded microfibers as a co-therapy strategy for glioblastoma treatment.

Malignant glioblastoma (GB) is the predominant primary brain tumour in adults, but despite the efforts towards novel therapies, the median survival of GB patients has not significantly improved in the last decades. Therefore, localised approaches that treat GB straight into the tumour site provide an alternative to enhance chemotherapy bioavailability and efficacy, reducing systemic toxicity. Likewise, the discovery of protein targets, such as the NIMA-related kinase 1 (Nek1), which was previously shown to be associated with temozolomide (TMZ) resistance in GB, has stimulated the clinical development of target therapy approaches to treat GB patients. In this study, we report an electrospun polyvinyl alcohol (PVA) microfiber (MF) brain-implant prepared for the controlled release of Nek1 protein inhibitor (iNek1) and TMZ or TMZ-loaded nanoparticles. The formulations revealed adequate stability and drug loading, which prolonged the drugs' release allowing a sustained exposure of the GB cells to the treatment and enhancing the drugs' therapeutic effects. TMZ-loaded MF provided the highest concentration of TMZ within the brain of tumour-bearing rats, and it was statistically significant when compared to TMZ via intraperitoneal (IP). All animals treated with either co-therapy formulation (TMZ + iNek1 MF or TMZ nanoparticles + iNek1 MF) survived until the endpoint (60 days), whereas the Blank MF (drug-unloaded), TMZ MF and TMZ IP-treated rats' median survival was found to be 16, 31 and 25 days, respectively. The tumour/brain area ratio of the rats implanted with either MF co-therapy was found to be reduced by 5-fold when compared to Blank MF-implanted rats. Taken together, our results strongly suggest that Nek1 is an important GB oncotarget and the inhibition of Nek1's activity significantly decreases GB cells' viability and tumour size when combined with TMZ treatment.

Is the degree of facial swelling after dental extraction sufficient to justify the current delays to radiotherapy mask production? A pilot evaluation of postextraction swelling using 3D photography.

BACKGROUND: Concern that facial swelling after dental extractions will spoil the fit of radiotherapy masks in head and neck cancer patients leads to the current practice of delay making of mask production (and therefore the start of radiotherapy) for several days or longer. However, there is little data on how extensive facial swelling is after dental extraction. AIM: To assess the degree of facial swelling in a group of adult patients attending Newcastle Dental School for routine dental extractions. MATERIALS AND METHODS: Seventeen dental extraction patients underwent three-dimensional photography using the 3dMDFace® system at 1-week preop, immediately preop, and at 48-h postop. We recorded demographic data, teeth extracted, and methods. Facial volume change was assessed using 3dMD Vultus® software. Two reviewers ran the data through the 3dMD Vultus® software independently. We used Student's t-test to assess significance. RESULTS: Twelve patients were included in the final analysis. There was no significant difference in the difference between the two preoperative measurements and the preoperative versus postoperative difference (Wilcoxon signed-rank test: Reviewer 1: p = .31. and Reviewer 2: p = .10). Thus, mean facial swelling was less than the threshold for significant swelling which was deemed to be 15 cm3 . CONCLUSION: Facial swelling following dental extraction may not be sufficient in itself to justify the current delays in mask production and subsequent delivery of radiotherapy. Further definitive studies are needed to optimize how dental extractions should be timed within head and neck cancer care pathways.

Dysregulation of ErbB4 Signaling Pathway in the Dorsal Hippocampus after Neonatal Hypoxia-Ischemia and Late Deficits in PV+ Interneurons, Synaptic Plasticity and Working Memory.

Neonatal hypoxic-ischemic (HI) injury leads to deficits in hippocampal parvalbumin (PV)+ interneurons (INs) and working memory. Therapeutic hypothermia (TH) does not prevent these deficits. ErbB4 supports maturation and maintenance of PV+ IN. Thus, we hypothesized that neonatal HI leads to persistent deficits in PV+ INs, working memory and synaptic plasticity associated with ErbB4 dysregulation despite TH. P10 HI-injured mice were randomized to normothermia (NT, 36 °C) or TH (31 °C) for 4 h and compared to sham. Hippocampi were studied for α-fodrin, glial fibrillary acidic protein (GFAP), and neuroregulin (Nrg) 1 levels; erb-b2 receptor tyrosine kinase 4 (ErbB4)/ Ak strain transforming (Akt) activation; and PV, synaptotagmin (Syt) 2, vesicular-glutamate transporter (VGlut) 2, Nrg1, and ErbB4 expression in coronal sections. Extracellular field potentials and behavioral testing were performed. At P40, deficits in PV+ INs correlated with impaired memory and coincided with blunted long-term depression (LTD), heightened long-term potentiation (LTP) and increased Vglut2/Syt2 ratio, supporting excitatory-inhibitory (E/I) imbalance. Hippocampal Nrg1 levels were increased in the hippocampus 24 h after neonatal HI, delaying the decline documented in shams. Paradoxically ErbB4 activation decreased 24 h and again 30 days after HI. Neonatal HI leads to persistent deficits in hippocampal PV+ INs, memory, and synaptic plasticity. While acute decreased ErbB4 activation supports impaired maturation and survival after HI, late deficit reemergence may impair PV+ INs maintenance after HI.

Measuring quality of hepatitis B care in a remote Australian Aboriginal community: opportunities for improvement.

BACKGROUND: Chronic hepatitis B (CHB) infection remains a significant public health issue for Indigenous Australians, in particular for remote communities. AIM: To evaluate the spectrum of hepatitis B virus (HBV) care provided to a remote Aboriginal community. Measures studied included screening, seroprevalence, vaccination rates and efficacy, and HCC risk and surveillance adherence. METHODS: A retrospective audit of HBV care received by all permanent residents currently attending a remote Aboriginal Health service. This study was endorsed by both the local Aboriginal Health service and the Aboriginal Health Council of South Australia. RESULTS: A total of 208 patients attended the clinic, of whom 52% (109) were screened for HBV. Of these, 12% (13) had CHB and 20% (22) had evidence of past infection. Similarly, of the 208 attending patients, complete vaccination was documented in 48% (99). Of the 33 patients with post-vaccination serology, 24% (8) had subtherapeutic (<10 IU/mL) levels of HBsAb. Subtherapeutic HBsAb was independently associated with higher Charlson Comorbidity scores (odds ratio = 17.1; 95% confidence interval 1.2-243.3; P = 0.036). Definitive breakthrough infection was identified in 6% (2) patients. One HBsAg positive patient was identified as needing HCC surveillance, but had not undertaken HCC surveillance. CONCLUSION: Opportunities to improve the quality of CHB care through increased HBV vaccination, screening and adherence to HCC surveillance were identified. High rates of subtherapeutic vaccine responses and documented breakthrough infection raises concerns about the effectiveness of current CHB vaccines in this population.

Machine Learning for Process Monitoring and Control of Hot-Melt Extrusion: Current State of the Art and Future Directions.

In the last few decades, hot-melt extrusion (HME) has emerged as a rapidly growing technology in the pharmaceutical industry, due to its various advantages over other fabrication routes for drug delivery systems. After the introduction of the 'quality by design' (QbD) approach by the Food and Drug Administration (FDA), many research studies have focused on implementing process analytical technology (PAT), including near-infrared (NIR), Raman, and UV-Vis, coupled with various machine learning algorithms, to monitor and control the HME process in real time. This review gives a comprehensive overview of the application of machine learning algorithms for HME processes, with a focus on pharmaceutical HME applications. The main current challenges in the application of machine learning algorithms for pharmaceutical processes are discussed, with potential future directions for the industry.

Development, Characterization and Cell Viability Inhibition of PVA Spheres Loaded with Doxorubicin and 4'-Amino-1-Naphthyl-Chalcone (D14) for Osteosarcoma.

Chalcones (1,3-diaryl-2-propen-1-ones) are naturally occurring polyphenols with known anticancer activity against a variety of tumor cell lines, including osteosarcoma (OS). In this paper, we present the preparation and characterization of spheres (~2 mm) from polyvinyl alcohol (PVA) containing a combination of 4'-Amino-1-Naphthyl-Chalcone (D14) and doxorubicin, to act as a new polymeric dual-drug anticancer delivery. D14 is a potent inhibitor of osteosarcoma progression and, when combined with doxorubicin, presents a synergetic effect; hence, physically crosslinked PVA spheres loaded with D14 and doxorubicin were prepared using liquid nitrogen and six freeze-thawing cycles. Physical-chemical characterization using a scanning electron microscope (SEM), differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD) presented that the drugs were incorporated into the spheres via weak interactions between the drugs and the polymeric chains, resulting in overall good drug stability. The cytotoxicity activity of the PVA spheres co-encapsulating both drugs was tested against the U2OS human osteosarcoma cell line by 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide (MTT) assay, and compared to the spheres carrying either D14 or doxorubicin alone. The co-delivery showed a cytotoxic effect 2.6-fold greater than doxorubicin alone, revealing a significant synergistic effect with a coefficient of drug interaction (CDI) of 0.49. The obtained results suggest this developed PVA sphere as a potential dual-drug delivery system that could be used for the prominent synergistic anticancer activity of co-delivering D14 and doxorubicin, providing a new potential strategy for improved osteosarcoma treatment.