Immunotherapy for HPV negative head and neck squamous cell carcinoma.

Head and neck cancer (HNSCC) is the 8th most common cancer in the UK, with incidence increasing due to lifestyle factors such as tobacco and alcohol abuse. HNSCC is an immune-suppressive disease characterised by impaired cytokine secretion and dysregulation of immune infiltrate. As such, immunotherapy is a potential treatment option, with therapeutic cancer vaccination demonstrating the greatest potential. The success of cancer vaccination is dependent on informed antigen selection: an ideal antigen must be either tumour-specific or tumour-associated, as well as highly immunogenic. Stratification of the patient population for antigen expression and validated biomarkers are also vital. This review focuses on the latest developments in immunotherapy, specifically the development of therapeutic vaccines, and highlights successes, potential drawbacks and areas for future development. Immunotherapy approaches considered for HNSCC include monoclonal antibodies (mAb), Oncolytic viral (OV) therapies, Immune Checkpoint Inhibitors (ICIs) and cancer vaccines.

Neoblast-like stem cells of Fasciola hepatica.

The common liver fluke (Fasciola hepatica) causes the disease fasciolosis, which results in considerable losses within the global agri-food industry. There is a shortfall in the drugs that are effective against both the adult and juvenile life stages within the mammalian host, such that new drug targets are needed. Over the last decade the stem cells of parasitic flatworms have emerged as reservoirs of putative novel targets due to their role in development and homeostasis, including at host-parasite interfaces. Here, we investigate and characterise the proliferating cells that underpin development in F. hepatica. We provide evidence that these cells are capable of self-renewal, differentiation, and are sensitive to ionising radiation- all attributes of neoblasts in other flatworms. Changes in cell proliferation were also noted during the early stages of in vitro juvenile growth/development (around four to seven days post excystment), which coincided with a marked reduction in the nuclear area of proliferating cells. Furthermore, we generated transcriptomes from worms following irradiation-based ablation of neoblasts, identifying 124 significantly downregulated transcripts, including known stem cell markers such as fgfrA and plk1. Sixty-eight of these had homologues associated with neoblast-like cells in Schistosoma mansoni. Finally, RNA interference mediated knockdown of histone h2b (a marker of proliferating cells), ablated neoblast-like cells and impaired worm development in vitro. In summary, this work demonstrates that the proliferating cells of F. hepatica are equivalent to neoblasts of other flatworm species and demonstrate that they may serve as attractive targets for novel anthelmintics.

Urethane dimethacrylate-based photopolymerizable resins for stereolithography 3D printing: A physicochemical characterisation and biocompatibility evaluation.

Vat photopolymerisation (VP) three-dimensional printing (3DP) has attracted great attention in many different fields, such as electronics, pharmaceuticals, biomedical devices and tissue engineering. Due to the low availability of biocompatible photocurable resins, its application in the healthcare sector is still limited. In this work, we formulate photocurable resins based on urethane dimethacrylate (UDMA) combined with three different difunctional methacrylic diluents named ethylene glycol dimethacrylate (EGDMA), di(ethylene glycol) dimethacrylate (DEGDMA) or tri(ethylene glycol) dimethacrylate (TEGDMA). The resins were tested for viscosity, thermal behaviour and printability. After printing, the 3D printed specimens were measured with a digital calliper in order to investigate their accuracy to the digital model and tested with FT-IR, TGA and DSC. Their mechanical properties, contact angle, water sorption and biocompatibility were also evaluated. The photopolymerizable formulations investigated in this work achieved promising properties so as to be suitable for tissue engineering and other biomedical applications.

A systematic review and meta-analysis assessing the use of tranexamic acid (TXA) in acute gastrointestinal bleeding.

INTRODUCTION: Gastrointestinal bleeding results in significant morbidity, cost and mortality. TXA, an antifibrinolytic agent, has been proposed to reduce mortality; however, many studies report conflicting results. METHODS: The aim of the study was to perform the first systematic review and meta-analysis of RCTs to evaluate the efficacy TXA for both upper and lower gastrointestinal bleeding. This was performed per PRISMA guidelines. PubMed, EMBASE, Cochrane and Scopus databases were searched for RCTs. Dichotomous variables were pooled as risk ratios (RR) with 95% confidence intervals (CI) using the MH method with random effects modelling. RESULTS: Fourteen RCTs were identified with 14,338 patients and mean age of 58.4 years. 34.9% (n = 5008) were female and 65.1% (n = 9330) male. There was no significant difference in mortality between TXA and placebo (RR 0.86 95% CI (0.74 to 1.00), P: 0.05). The secondary outcomes, similarly, did not yield significant results. These included rebleeding, need for surgical intervention (RR: 0.75 95% CI (0.53, 1.07)), endoscopic intervention (RR: 0.92 95% CI (0.70, 1.22)), transfusion requirement (RR: 1.01 95% CI (0.94, 10.7)) and length of stay (RR: 0.03 95% CI (- 0.03, 0.08)). There was no increased risk of VTE, RR: 1.29 95% CI (0.53, 3.16). One trial (n = 12,009) reported an increased risk of seizure in the TXA group, RR: 1.73 95% CI (1.03-2.93). CONCLUSION: TXA does not reduce mortality in patients with acute upper or lower gastrointestinal bleeding and may confer an increased risk of seizures. The authors do not recommend the use of TXA in acute gastrointestinal bleeding.

Induction of double-strand breaks with the non-steroidal androgen receptor ligand flutamide in patients on androgen suppression: a study protocol for a randomized, double-blind prospective trial.

BACKGROUND: Prostate cancer remains the most prevalent malignancy and the second-leading cause of cancer-related death in men in the USA. Radiation therapy, typically with androgen suppression, remains a mainstay in the treatment of intermediate- and high-risk, potentially lethal prostate cancers. However, local recurrence and treatment failure remain common. Basic and translational research has determined the potential for using androgen receptor (AR) ligands (e.g., dihydrotestosterone and flutamide) in the context of androgen-deprived prostate cancer to induce AR- and TOP2B-mediated DNA double-strand breaks (DSBs) and thereby synergistically enhance the effect of radiation therapy (RT). The primary aim of this study is to carry out pharmacodynamic translation of these findings to humans. METHODS: Patients with newly diagnosed, biopsy-confirmed localized prostatic adenocarcinoma will be recruited. Flutamide, an oral non-steroidal androgen receptor ligand, will be administered orally 6-12 h prior to prostate biopsy (performed under anesthesia prior to brachytherapy seed implantation). Key study parameters will include the assessment of DNA double-strand breaks by γH2A.x foci and AR localization to the nucleus. The initial 6 patients will be treated in a single-arm run-in phase to assess futility by establishing whether at least 2 subjects from this group develop γH2A.x foci in prostate cancer cells. If this criterion is met, the study will advance to a two-arm, randomized controlled phase in which 24 participants will be randomized 2:1 to either flutamide intervention or placebo standard-of-care (with all patients receiving definitive brachytherapy). The key pharmacodynamic endpoint will be to assess whether the extent of γH2A.x foci (proportion of cancer cells positive and number of foci per cancer cell) is greater in patients receiving flutamide versus placebo. Secondary outcomes of this study include an optional, exploratory analysis that will (a) describe cancer-specific methylation patterns of cell-free DNA in plasma and urine and (b) assess the utility of serum and urine samples as a DNA-based biomarker for tracking therapeutic response. DISCUSSION: This study will confirm in humans the pharmacodynamic effect of AR ligands to induce transient double-strand breaks when administered in the context of androgen deprivation as a novel therapy for prostate cancer. The findings of this study will permit the development of a larger trial evaluating flutamide pulsed-dose sequencing in association with fractionated external beam RT (+/- brachytherapy). The study is ongoing, and preliminary data collection and recruitment are underway; analysis has yet to be performed. TRIAL REGISTRATION: ClinicalTrials.gov NCT03507608. Prospectively registered on 25 April 2018.

FLASH Effects Induced by Orthovoltage X-Rays.

PURPOSE: This work describes the first implementation and in vivo study of ultrahigh-dose-rate radiation (>37 Gy/s; FLASH) effects induced by kilovoltage (kV) x-ray from a rotating-anode x-ray source. METHODS AND MATERIALS: A high-capacity rotating-anode x-ray tube with an 80-kW generator was implemented for preclinical FLASH radiation research. A custom 3-dimensionally printed immobilization and positioning tool was developed for reproducible irradiation of a mouse hind limb. Calibrated Gafchromic (EBT3) film and thermoluminescent dosimeters (LiF:Mg,Ti) were used for in-phantom and in vivo dosimetry. Healthy FVB/N and FVBN/C57BL/6 outbred mice were irradiated on 1 hind leg to doses up to 43 Gy at FLASH (87 Gy/s) and conventional (CONV; <0.05 Gy/s) dose rates. The radiation doses were delivered using a single pulse with the widths up to 500 ms and 15 minutes at FLASH and CONV dose rates. Histologic assessment of radiation-induced skin damage was performed at 8 weeks posttreatment. Tumor growth suppression was assessed using a B16F10 flank tumor model in C57BL6J mice irradiated to 35 Gy at both FLASH and CONV dose rates. RESULTS: FLASH-irradiated mice experienced milder radiation-induced skin injuries than CONV-irradiated mice, visible by 4 weeks posttreatment. At 8 weeks posttreatment, normal tissue injury was significantly reduced in FLASH-irradiated animals compared with CONV-irradiated animals for histologic endpoints including inflammation, ulceration, hyperplasia, and fibrosis. No difference in tumor growth response was observed between FLASH and CONV irradiations at 35 Gy. The normal tissue sparing effects of FLASH irradiations were observed only for high-severity endpoint of ulceration at 43 Gy, which suggests the dependency of biologic endpoints to FLASH radiation dose. CONCLUSIONS: Rotating-anode x-ray sources can achieve FLASH dose rates in a single pulse with dosimetric properties suitable for small-animal experiments. We observed FLASH normal tissue sparing of radiation toxicities in mouse skin irradiated at 35 Gy with no sacrifice to tumor growth suppression. This study highlights an accessible new modality for laboratory study of the FLASH effect.

Combining EZH2 and HDAC inhibitors to target castration-resistant prostate cancers.

Development of resistance in castration-resistant prostate cancer (CRPC) involves epigenetic pathways. A new study in PLOS Biology demonstrates that combined therapy targeting enhancer of zeste homolog 2 (EZH2) and histone deacetylases (HDACs) may sensitize CRPC to both epigenetic and standard therapies.

Microfluidic technologies in tumour metabolism.

The tumour microenvironment presents many challenges in the development and evaluation of new anti-cancer therapeutics. Enhanced understanding of the unique metabolic characteristics of cancer cells could provide valuable knowledge to develop broad-spectrum anti-neoplastic agents with reduced systemic toxicity. However, a major limitation is the lack of physiological relevance of many conventional in vitro models. Emerging microfluidic platform technologies, hold the potential of recapitulating the physiological and pathological features of the tumour microenvironment, thus increasing the relevance of pre-clinical experimental data. With precise manipulation of physical and chemical properties, the microfluidic based, tumour-on-chip authentically replicates the tumour growth environment, potentially helping accelerate the pre-clinical screening of novel anti-tumour drug combinations. Additionally, nanoscale vehicles produced using microfluidic technologies, offer an emerging solution to modulate the hydrophilicity and release kinetics of drugs that in the free state exhibit challenging pharmacokinetics. This article will review the current state-of-the-art in this space and outline important challenges that are yet to be overcome.

Operating on the Mesentery in Robotic Colonic Surgery-General Techniques.

During colorectal surgery the mesentery is the organ on which the greatest amount of operating time is focused. It has recently gained increasing attention. This technical review focuses on the mesentery during robotic colonic procedures. Specifically, we focus upon how to access, dissect, and divide the mesentery using the robotic platform. We also touch on the management of bleeding and some specific disease etiologies.

What Is Wrong with the International Holocaust Remembrance Alliance's Definition of Antisemitism?

The International Holocaust Remembrance Alliance (IHRA) developed a 'Working Definition of Antisemitism' in 2016. Whilst the definition has received a significant amount of media attention, we are not aware of any comprehensive philosophical analysis. This article analyses this definition. We conclude that the definition and its list of examples ought to be rejected. The urgency to do so stems from the fact that pro-Israel activists can and have mobilised the IHRA document for political goals unrelated to tackling antisemitism, notably to stigmatise and silence critics of the Israeli government. This causes widespread self-censorship, has an adverse impact on freedom of speech, and impedes action against the unjust treatment of Palestinians. We also identify intrinsic problems in the way the definition refers to criticism of Israel similar 'to that leveled against any other country', ambiguous wording about 'the power of Jews as a collective', lack of clarity as to the Jewish people's 'right to self-determination', and its denial of obvious racism. We consider alternative definitions and prefer one like the Oxford English Dictionary (OED) definition, 'hostility to or prejudice against Jews', with the addition of the words 'as Jews'. We recognise that the Jerusalem Declaration on Antisemitism (JDA) can play a useful purpose in illustrating the shortcomings of the IHRA definition. However, we do not advocate promoting it as the prime international definition. Indeed, we question the efficacy of using complex new definitions to combat racism against Jews or other groups, and instead advocate combatting it through collective action across societies.

Identifying Phased Mutations and Complex Rearrangements in Human Prostate Cancer Cell Lines through Linked-Read Whole-Genome Sequencing.

A limited number of cell lines have fueled the majority of preclinical prostate cancer research, but their genomes remain incompletely characterized. Here, we utilized whole-genome linked-read sequencing for comprehensive characterization of phased mutations and rearrangements in the most commonly used cell lines in prostate cancer research including PC3, LNCaP, DU145, CWR22Rv1, VCaP, LAPC4, MDA-PCa-2b, RWPE-1, and four derivative castrate-resistant (CR) cell lines LNCaP_Abl, LNCaP_C42b, VCaP-CR, and LAPC4-CR. Phasing of mutations allowed determination of "gene-level haplotype" to assess whether genes harbored heterozygous mutations in one or both alleles. Phased structural variant analysis allowed identification of complex rearrangement chains consistent with chromothripsis and chromoplexy. In addition, comparison of parental and derivative CR lines revealed previously known and novel genomic alterations associated with the CR phenotype. IMPLICATIONS: This study therefore comprehensively characterized phased genomic alterations in the commonly used prostate cancer cell lines, providing a useful resource for future prostate cancer research.

Sox2 induces glioblastoma cell stemness and tumor propagation by repressing TET2 and deregulating 5hmC and 5mC DNA modifications.

DNA methylation is a reversible process catalyzed by the ten-eleven translocation (TET) family of enzymes (TET1, TET2, TET3) that convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). Altered patterns of 5hmC and 5mC are widely reported in human cancers and loss of 5hmC correlates with poor prognosis. Understanding the mechanisms leading to 5hmC loss and its role in oncogenesis will advance the development of epigenetic-based therapeutics. We show that TET2 loss associates with glioblastoma (GBM) stem cells and correlates with poor survival of GBM patients. We further identify a SOX2:miR-10b-5p:TET2 axis that represses TET2 expression, represses 5hmC, increases 5mC levels, and induces GBM cell stemness and tumor-propagating potential. In vivo delivery of a miR-10b-5p inhibitor that normalizes TET2 expression and 5hmC levels inhibits tumor growth and prolongs survival of animals bearing pre-established orthotopic GBM xenografts. These findings highlight the importance of TET2 and 5hmC loss in Sox2-driven oncogenesis and their potential for therapeutic targeting.

Mechanisms, Challenges, and Opportunities in Combined Radiation and Hormonal Therapies.

Androgen receptor signaling blockade is perhaps the first example of targeted therapy in the treatment of cancer. Since the initial observations that prostate cancers depend on hormone signaling, hormonal therapies remain a cornerstone in the treatment of metastatic prostate cancer. Androgen deprivation therapy has been shown to improve outcomes involving treatment of prostate cancers with radiotherapy, though a mechanistic understanding into the optimal sequencing of androgen deprivation therapy and radiotherapy remains incomplete. In this review we highlight key clinical trials designed to study combinations of hormonal and radiotherapies and introduce recent discoveries into the complex biology of androgen receptor signaling and DNA damage and repair. These emerging mechanistic and translational studies may have profound implications on both our understanding of hormonal therapy and radiotherapy combinations and the development of novel treatment strategies for locally-advanced and metastatic castrate resistant prostate cancer.

Formulating RALA/Au nanocomplexes to enhance nanoparticle internalisation efficiency, sensitising prostate tumour models to radiation treatment.

BACKGROUND: Gold nanoparticles (AuNP) are effective radiosensitisers, however, successful clinical translation has been impeded by short systemic circulation times and poor internalisation efficiency. This work examines the potential of RALA, a short amphipathic peptide, to enhance the uptake efficiency of negatively charged AuNPs in tumour cells, detailing the subsequent impact of AuNP internalisation on tumour cell radiation sensitivity. RESULTS: RALA/Au nanoparticles were formed by optimising the ratio of RALA to citrate capped AuNPs, with assembly occurring through electrostatic interactions. Physical nanoparticle characteristics were determined by UV-vis spectroscopy and dynamic light scattering. Nano-complexes successfully formed at w:w ratios > 20:1 (20 µg RALA:1 µg AuNP) yielding positively charged nanoparticles, sized < 110 nm with PDI values < 0.52. ICP-MS demonstrated that RALA enhanced AuNP internalisation by more than threefold in both PC-3 and DU145 prostate cancer cell models, without causing significant toxicity. Importantly, all RALA-AuNP formulations significantly increased prostate cancer cell radiosensitivity. This effect was greatest using the 25:1 RALA-AuNP formulation, producing a dose enhancement effect (DEF) of 1.54 in PC3 cells. Using clinical radiation energies (6 MV) RALA-AuNP also significantly augmented radiation sensitivity. Mechanistic studies support RALA-AuNP nuclear accumulation resulting in increased DNA damage yields. CONCLUSIONS: This is the first study to demonstrate meaningful radiosensitisation using low microgram AuNP treatment concentrations. This effect was achieved using RALA, providing functional evidence to support our previous imaging study indicating RALA-AuNP nuclear accumulation.

Oncogenic gene fusions in nonneoplastic precursors as evidence that bacterial infection can initiate prostate cancer.

Prostate adenocarcinoma is the second most commonly diagnosed cancer in men worldwide, and the initiating factors are unknown. Oncogenic TMPRSS2:ERG (ERG+) gene fusions are facilitated by DNA breaks and occur in up to 50% of prostate cancers. Infection-driven inflammation is implicated in the formation of ERG+ fusions, and we hypothesized that these fusions initiate in early inflammation-associated prostate cancer precursor lesions, such as proliferative inflammatory atrophy (PIA), prior to cancer development. We investigated whether bacterial prostatitis is associated with ERG+ precancerous lesions in unique cases with active bacterial infections at the time of radical prostatectomy. We identified a high frequency of ERG+ non-neoplastic-appearing glands in these cases, including ERG+ PIA transitioning to early invasive cancer. These lesions were positive for ERG protein by immunohistochemistry and ERG messenger RNA by in situ hybridization. We additionally verified TMPRSS2:ERG genomic rearrangements in precursor lesions using tricolor fluorescence in situ hybridization. Identification of rearrangement patterns combined with whole-prostate mapping in three dimensions confirmed multiple (up to eight) distinct ERG+ precancerous lesions in infected cases. We further identified the pathogen-derived genotoxin colibactin as a potential source of DNA breaks in clinical cases as well as cultured prostate cells. Overall, we provide evidence that bacterial infections can initiate driver gene alterations in prostate cancer. In addition, our observations indicate that infection-induced ERG+ fusions are an early alteration in the carcinogenic process and that PIA may serve as a direct precursor to prostate cancer.

Hypoxia-targeted cupric-tirapazamine liposomes potentiate radiotherapy in prostate cancer spheroids.

In this study, novel cupric-tirapazamine [Cu(TPZ)2]-liposomes were developed as an effective hypoxia-targeted therapeutic, which potentiated radiotherapy in a three dimensional (3D) prostate cancer (PCa) model. To overcome the low water solubility of the Cu(TPZ)2, a remote loading method was developed to efficiently load the lipophilic complex into different liposomal formulations. The effect of pH, temperature, PEGylation, lipid composition, liposome size, lipid: complex ratio on the liposome properties, and drug loading was evaluated. The highest loading efficiency was obtained at neutral pH, which was independent of lipid composition and incubation time. In addition, enhanced drug loading was achieved upon decreasing the lipid:complex molar ratio with minimal effects on liposomes' morphology. Interestingly, the in vitro potency of the developed liposomes was easily manipulated by changing the lipid composition. The hydrophilic nature of our liposomal formulations improved the complex's solubility, leading to enhanced cellular uptake and toxicity, both in PCa monolayers and tumour spheroids. Moreover, Cu(TPZ)2-loaded liposomes combined with radiation, showed a significant reduction in PCa spheroids growth rate, compared to the free complex or radiation alone, which could potentiate radiotherapy in patients with localised advanced PCa.

Novel tip-loaded dissolving and implantable microneedle array patches for sustained release of finasteride.

Finasteride (FND) is a competitive inhibitor of 5α-reductase, an enzyme involved in benign prostatic hyperplasia (BPH) and androgenic alopecia. FND is administered in oral, often lifelong treatments, increasing the pill burden of polymedicated patients. Microneedle array patches (MAPs) are minimally invasive devices that painlessly pierce the outermost layers of the skin, forming slowly-dissolving drug depots in the dermis, which can release drugs over weeks or months, making this platform an attractive, patient-friendly option for long-term treatments. This work describes the development of long-acting dissolving and implantable PLGA MAPs aimed for systemic release of FND for at least two weeks. Mechanically strong tip-loaded MAPs with pyramidal geometry were obtained using micromoulding methodology. In vitro studies revealed that the dissolving and implantable MAPs were able to release the drug for over 7 and 14 days, respectively. Skin deposition experiments in Franz cells demonstrated that after 24 h, dissolving and implantable MAPs were able to deposit 629.00 ± 214.54 µg and 1861.64 ± 383.30 µg of FND in the skin, respectively. On the other hand, transdermal permeation studies showed that both formulations produced a slow release of the drug to the receptor compartment of the Franz cells, with dissolving and implantable MAPs releasing 90.43 ± 6.20 µg and 27.80 ± 3.94 µg of FND after 24 h. The formulations described here could be an alternative to current oral treatments, having the potential to deliver the drug for extended periods, simplifying the treatment of BPH and androgenic alopecia.

A meta-analysis of the use of intraoperative cholangiography; time to revisit our approach to cholecystectomy?

BACKGROUND: Despite some evidence of improved survival with intraoperative cholangiography during cholecystectomy, debate has raged about its benefit, in part because of its questionable benefit, time, and resources required to complete. METHODS: An International Prospective Register of Systematic Reviews-registered (ID CRD42018102154) meta-analysis following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines using PubMed, Scopus, Web of Science, and Cochrane library from 2003 to 2018 was undertaken including search strategy "intraoperative AND cholangiogra* AND cholecystectomy." Articles scoring ≥ 16 for comparative and ≥ 10 for noncomparative using the Methodological Index for Non-Randomized Studies criteria were included. A dichotomous random effects meta-analysis using the Mantel-Haenszel method performed on Review Manager Version 5.3 was carried out. RESULTS: Of 2,059 articles reviewed, 62 met criteria for final analysis. The mean rate of intraoperative cholangiography was 38.8% (range 1.6%-96.4%).There was greater detection of bile duct stones during cholecystectomy with routine intraoperative cholangiography compared with selective intraoperative cholangiography (odds ratio = 3.28, confidence interval = 2.80-3.86, P value < .001). While bile duct injury during cholecystectomy was less with intraoperative cholangiography (0.39%) than without intraoperative cholangiography (0.43%), it was not statistically significant (odds ratio = 0.88, confidence interval = 0.65-1.19, P value = .41). Readmission following cholecystectomy with intraoperative cholangiography was 3.0% compared to 3.5% without intraoperative cholangiography (odds ratio = 0.91, confidence interval = 0.78-1.06, P value = .23). CONCLUSION: The use of intraoperative cholangiography still has its place in cholecystectomy based on the detection of choledocholithiasis and the potential reduction of unfavorable outcomes associated with common bile duct stones. This meta-analysis, the first to review intraoperative cholangiography use, identified a marked variation in cholangiography use. Retrospective studies limit the ability to critically define association between intraoperative cholangiography use and bile duct injury.

Exploiting the anticancer effects of a nitrogen bisphosphonate nanomedicine for glioblastoma multiforme.

Glioblastoma multiforme (GBM) is an incurable aggressive brain cancer in which current treatment strategies have demonstrated limited survival benefit. In recent years, nitrogen-containing bisphosphonates (N-BPs) have demonstrated direct anticancer effects in a number of tumour types including GBM. In this study, a nano-formulation with the RALA peptide was used to complex the N-BP, alendronate (ALN) into nanoparticles (NPs) < 200 nm for optimal endocytic uptake. Fluorescently labelled AlexaFluor®647 Risedronate was used as a fluorescent analogue to visualise the intracellular delivery of N-BPs in both LN229 and T98G GBM cells. RALA NPs were effectively taken up by GBM where a dose-dependent response was evidenced with potentiation factors of 14.96 and 13.4 relative to ALN alone after 72 h in LN229 and T98G cells, respectively. Furthermore, RALA/ALN NPs at the IC50, significantly decreased colony formation, induced apoptosis and slowed spheroid growth in vitro. In addition, H-Ras membrane localisation was significantly reduced in the RALA/ALN groups compared to ALN or controls, indicative of prenylation inhibition. The RALA/ALN NPs were lyophilised to enhance stability without compromising the physiochemical properties necessary for functionality, highlighting the suitability of the NPs for scale-up and in vivo application. Collectively, these data show the significant potential of RALA/ALN NPs as novel therapeutics in the treatment of GBM.

Radiation Response in the Tumour Microenvironment: Predictive Biomarkers and Future Perspectives.

Radiotherapy (RT) is a primary treatment modality for a number of cancers, offering potentially curative outcomes. Despite its success, tumour cells can become resistant to RT, leading to disease recurrence. Components of the tumour microenvironment (TME) likely play an integral role in managing RT success or failure including infiltrating immune cells, the tumour vasculature and stroma. Furthermore, genomic profiling of the TME could identify predictive biomarkers or gene signatures indicative of RT response. In this review, we will discuss proposed mechanisms of radioresistance within the TME, biomarkers that may predict RT outcomes, and future perspectives on radiation treatment in the era of personalised medicine.