Combinatorial functionomics identifies HDAC6-dependent molecular vulnerability of radioresistant head and neck cancer.

Background: Radiotherapy is the primary treatment modality for most head and neck cancers (HNCs). Despite the addition of chemotherapy to radiotherapy to enhance its tumoricidal effects, almost a third of HNC patients suffer from locoregional relapses. Salvage therapy options for such recurrences are limited and often suboptimal, partly owing to divergent tumor and microenvironmental factors underpinning radioresistance.

Genomic and transcriptomic profiling of radioresistant prostate and head and neck cancers implicate a BAHD1-dependent modification of DNA damage at the heterochromatin.

Radiotherapy is an integral modality in treating human cancers, but radioresistance remains a clinical challenge due to the involvement of multiple intrinsic cellular and extrinsic tumour microenvironment factors that govern radiosensitivity. To study the intrinsic factors that are associated with cancer radioresistance, we established 4 radioresistant prostate (22Rv1 and DU145) and head and neck cancer (FaDu and HK1) models by irradiating their wild-type parentals to 90 Gy, mimicking the fractionated radiotherapy schema that is often using in the clinic, and performed whole exome and transcriptome sequencing of the radioresistant and wild-type models. Comparative genomic analyses detected the enrichment of mismatch repair mutational signatures (SBS6, 14, 15, 20) across all the cell lines and several non-synonymous single nucleotide variants involved in pro-survival pathways.

The Proteogenomics of Prostate Cancer Radioresistance.

Unlabelled: Prostate cancer is frequently treated with radiotherapy. Unfortunately, aggressive radioresistant relapses can arise, and the molecular underpinnings of radioresistance are unknown. Modern clinical radiotherapy is evolving to deliver higher doses of radiation in fewer fractions (hypofractionation).

Improving the therapeutic ratio of radiotherapy against radioresistant cancers: Leveraging on novel artificial intelligence-based approaches for drug combination discovery.

Despite numerous advances in cancer radiotherapy, tumor radioresistance remain one of the major challenges limiting treatment efficacy of radiotherapy. Conventional strategies to overcome radioresistance involve understanding the underpinning molecular mechanisms, and subsequently using combinatorial treatment strategies involving radiation and targeted drug combinations against these radioresistant tumors. These strategies exploit and target the molecular fingerprint and vulnerability of the radioresistant clones to achieve improved efficacy in tumor eradication.

Stealthiness and Hematocompatibility of Gold Nanoparticles with Pre-Formed Protein Corona.

Studies have established that a serum protein corona pre-formed around gold nanorods (NRs) could be exploited for loading photosensitizers and chemotherapeutics to result in efficient cell kill with an extremely low dose. In this study, we further demonstrated that pre-forming a serum protein corona (PC) around citrate-capped NRs (NR-Cit) to form NR-PC conferred them stealth property and high hematocompatibility similar to the common strategy of PEGylating NRs, which would otherwise not be able to evade the immune system. Specifically, the NR-PC caused minimal complement activation with significantly lower formation of the terminal complement complex SC5b-9 measured in human serum containing NR-PC, and this resulted in low uptake by phagocytic U937 monocytes of 5.

Dosimetric uncertainties impact on cell survival curve with low energy proton.

There is an increasing number of radiobiological experiments being conducted with low energy protons (less than 5 MeV) for radiobiological studies due to availability of sub-millimetre focused beam. However, low energy proton has broad microdosimetric spectra which can introduce dosimetric uncertainty. In this work, we quantify the impact of this dosimetric uncertainties on the cell survival curve and how it affects the estimation of the alpha and beta parameters in the LQ formalism.

High-Dimensional Characterization of the Systemic Immune Landscape Informs on Synergism Between Radiation Therapy and Immune Checkpoint Blockade.

Purpose: Improved antitumor responses have been observed in patients after combination radiation therapy (RT) and immune checkpoint blockade (ICB). Whether these clinical responses are linked to the host systemic immune system has not been elucidated.

Methods And Materials: In this single-institution prospective observational study, peripheral blood was longitudinally collected from 10 patients with metastatic disease who had responded to anti-PD-1/anti-PD-L1 ICB and received RT (8-50 Gy in 1-5 fractions) upon disease progression at the following timepoints: baseline (pre-RT), 1 to 2 weeks post-RT, and post-ICB (cycle 1) on reintroduction post-RT.

Germline Polymorphisms and Length of Survival of Nasopharyngeal Carcinoma: An Exome-Wide Association Study in Multiple Cohorts.

Germline polymorphisms are linked with differential survival outcomes in cancers but are not well studied in nasopharyngeal carcinoma (NPC). Here, a two-phase association study is conducted to discover germline polymorphisms that are associated with the prognosis of NPC. The discovery phase includes two consecutive hospital cohorts of patients with NPC from Southern China.

Upconversion superballs for programmable photoactivation of therapeutics.

Upconversion nanoparticles (UCNPs) are the preferred choice for deep-tissue photoactivation, owing to their unique capability of converting deep tissue-penetrating near-infrared light to UV/visible light for photoactivation. Programmed photoactivation of multiple molecules is critical for controlling many biological processes. However, syntheses of such UCNPs require epitaxial growth of multiple shells on the core nanocrystals and are highly complex/time-consuming.

Mannitol-induced gold nanoparticle aggregation for the ligand-free detection of viral particles.

Traditional virus detection methods require ligands that bind to either viral capsid proteins or viral nucleic acids. Ligands are typically antibodies or oligonucleotides and they are expensive, have limited chemical stability, and can only detect one specific type of virus at a time. Here, the biochemical surface properties of viruses are exploited for ligand-free, nonspecific virus detection.

Vandetanib sensitizes head and neck squamous cell carcinoma to photodynamic therapy through modulation of EGFR-dependent DNA repair and the tumour microenvironment.

Background: Epidermal growth factor receptor (EGFR) overexpression is characteristic in head and neck cancers and is associated with tumour regrowth following photodynamic therapy (PDT).

Purpose: We investigated vandetanib, which selectively blocks EGFR and vascular endothelial growth factor receptor-2 (VEGFR-2), to enhance the efficacy of PDT.

Methods: We assessed the in vitro therapeutic efficacy of: 1) vandetanib; 2) PDT with the photosensitizer Chlorin e6 (Fotolon®); and 3) combined PDT + vadetanib treatment in CAL-27 oral squamous cell carcinoma (OSCC) cell line by cell viability, γH2AX foci immunostaining, cell cycle arrest and western blot.

Intra-patient and inter-patient comparisons of DNA damage response biomarkers in Nasopharynx Cancer (NPC): analysis of NCC0901 randomised controlled trial of induction chemotherapy in locally advanced NPC.

Background: Inter-patient heterogeneity in radiation-induced DNA damage responses is proposed to reflect intrinsic variations in tumour and normal tissue radiation sensitivity, but the prediction of phenotype by a molecular biomarker is influenced by clinical confounders and assay reproducibility. Here, we characterised the intrapatient and inter-patient heterogeneity in biomarkers of DNA damage and repair and radiation-induced apoptosis.

Methods: We enrolled 85 of 172 patients with locally advanced nasopharynx cancer from a randomised controlled phase II/III trial of induction chemotherapy added to chemo-radiotherapy.

Polydopamine Nanoparticles Enhance Drug Release for Combined Photodynamic and Photothermal Therapy.

Our study shows a facile two-step method which does not require the use of core templates to load a hydrophobic photosensitizer drug chlorin e6 (Ce6) within polydopamine (PDA) nanoparticles (NPs) while maintaining the intrinsic surface properties of PDA NPs. This structure is significantly different from hollow nanocapsules which are less stiff as they do not possess a core. To our knowledge, there exist no similar studies in the literature on drug loading within the polymer matrix of PDA NPs.

Combinatorial strategies of radiotherapy and immunotherapy in nasopharyngeal carcinoma.

Immunotherapy and radiation therapy (RT) have each demonstrated clinical success in the treatment of nasopharyngeal carcinoma (NPC) when utilized independently. Several characteristics of NPC make it particularly well suited for immunotherapeutic strategies, such as the association with viral infections like EBV and human papilloma virus (HPV), upregulation of PD-L1 expression, and the high number of tumor infiltrating lymphocytes. Immune checkpoint blockade is one such immunotherapeutic strategy that is gaining popularity rapidly.

Protein corona in drug delivery for multimodal cancer therapy in vivo.

The protein corona is inevitably formed on nanoparticles (NPs) when they are introduced in vivo and has been associated with a reduction in targeting yield, immune recognition and rapid blood clearance, leading to poor tumor accumulation. We have recently shown that it is possible to exploit the protein corona for drug delivery by exploiting it for loading and triggering the release of a photosensitizer Chlorin e6 (Ce6) for simultaneous photodynamic (PDT) and photothermal therapy (PTT) in vitro. Here, we extended our previous in vitro studies to evaluate its effectiveness in vivo.

Protein Corona around Gold Nanorods as a Drug Carrier for Multimodal Cancer Therapy.

A single nanodevice based on gold nanorods (NRs) coloaded with a photosensitizer, Chlorin e6 (Ce6), and a chemotherapeutic, Doxorubicin (Dox), on its endogenously formed human serum (HS) protein corona, i.e., NR-HS-Ce6-Dox was developed with the aim of performing multimodal cancer therapy: photodynamic (PDT), photothermal (PTT) and chemotherapy (CTX) simultaneously upon irradiation with a single 665 nm laser.

Exploiting the Protein Corona from Cell Lysate on DNA Functionalized Gold Nanoparticles for Enhanced mRNA Translation.

This study describes the use of DNA functionalized gold nanoparticles (AuNPs) to enhance the synthesis of proteins in cell lysate and examines the mechanisms behind the enhanced mRNA translation. With an appropriate DNA oligomer sequence that hybridizes to the 3'-untranslated region of two mRNA of interest, insulin and green fluorescent protein (GFP), we found that these DNA conjugated AuNPs (AuNP-DNA) introduced into HeLa cell lysate enhanced the synthesis of insulin and GFP by up to 2.18 and 1.

Exploiting the protein corona around gold nanorods for low-dose combined photothermal and photodynamic therapy.

A nanodevice comprising human serum (HS) protein corona coated gold nanorods (NRs) has been developed to perform both photothermal therapy (PTT) and photodynamic therapy (PDT) simultaneously at a very low dose under irradiation by a single laser. Here, we exploit the protein corona to load a photosensitizer, chlorin e6 (Ce6), to form NR-HS-Ce6, whose excitation wavelength matches with the longitudinal surface plasmon resonance (LSPR) of NRs. When excited by a single laser, the NRs caused photothermal ablation of cancer cells while Ce6 simultaneously produced reactive oxygen species (ROS) to kill cancer cells through oxidative stress in PDT.

An instantaneous colorimetric protein assay based on spontaneous formation of a protein corona on gold nanoparticles.

Commercial protein assays used ubiquitously in laboratories typically require long incubation times due to the inherently slow protein-reagent reactions. In this study, we report a novel facile technique for the instantaneous measurement of total protein concentration by exploiting the rapid aggregation dynamics of gold nanoparticles (NPs). By adsorbing different amounts of proteins on their surface to form a protein corona, these NPs can be sterically stabilized to different degrees by aggregation, thus exhibiting a spectrum of color change which can be quantitatively characterized by UV-Vis absorption spectroscopy.

Dark-field circular depolarization optical coherence microscopy.

Optical coherence microscopy (OCM) is a widely used structural imaging modality. To extend its application in molecular imaging, gold nanorods are widely used as contrast agents for OCM. However, they very often offer limited sensitivity as a result of poor signal to background ratio.

Nanoparticle interface to biology: applications in probing and modulating biological processes.

Nanomaterials can be considered as "pseudo" subcellular entities that are similar to endogenous biomolecules because of their size and ability to interact with other biomolecules. The interaction between nanoparticles and biomolecules gives rise to the nano-bio interface between a nanoparticle and its biological environment. This is often defined in terms of the biomolecules that are present on the surface of the nanoparticles.