The functional GRHL3-filaggrin axis maintains a tumor differentiation potential and influences drug sensitivity.

Current therapies for treating heterogeneous cancers such as head and neck squamous cell carcinoma (HNSCC) are non-selective and are administered independent of response biomarkers. Therapy resistance subsequently emerges, resulting in increased cellular proliferation that is associated with loss of differentiation. Whether a cancer cell differentiation potential can dictate therapy responsiveness is still currently unknown. A multi-omic approach integrating whole-genome and whole-transcriptome sequencing with drug sensitivity was employed in a HNSCC mouse model, primary patients' data, and human cell lines to assess the potential of functional differentiation in predicting therapy response. Interestingly, a subset of HNSCC with effective GRHL3-dependent differentiation was the most sensitive to inhibitors of PI3K/mTOR, c-Myc, and STAT3 signaling. Furthermore, we identified the GRHL3-differentiation target gene Filaggrin (FLG) as a response biomarker and more importantly, stratified HNSCC subsets as treatment resistant based on their FLG mutational profile. The loss of FLG in sensitive HNSCC resulted in a dramatic resistance to targeted therapies while the GRHL3-FLG signature predicted a favorable patient prognosis. This study provides evidence for a functional GRHL3-FLG tumor-specific differentiation axis that regulates targeted therapy response in HNSCC and establishes a rationale for clinical investigation of differentiation-paired targeted therapy in heterogeneous cancers.

YBX1 integration of oncogenic PI3K/mTOR signalling regulates the fitness of malignant epithelial cells.

In heterogeneous head and neck cancer (HNC), subtype-specific treatment regimens are currently missing. An integrated analysis of patient HNC subtypes using single-cell sequencing and proteome profiles reveals an epithelial-mesenchymal transition (EMT) signature within the epithelial cancer-cell population. The EMT signature coincides with PI3K/mTOR inactivation in the mesenchymal subtype. Conversely, the signature is suppressed in epithelial cells of the basal subtype which exhibits hyperactive PI3K/mTOR signalling. We further identify YBX1 phosphorylation, downstream of the PI3K/mTOR pathway, restraining basal-like cancer cell proliferation. In contrast, YBX1 acts as a safeguard against the proliferation-to-invasion switch in mesenchymal-like epithelial cancer cells, and its loss accentuates partial-EMT and in vivo invasion. Interestingly, phospho-YBX1 that is mutually exclusive to partial-EMT, emerges as a prognostic marker for overall patient outcomes. These findings create a unique opportunity to sensitise mesenchymal cancer cells to PI3K/mTOR inhibitors by shifting them towards a basal-like subtype as a promising therapeutic approach against HNC.

The Balance between Differentiation and Terminal Differentiation Maintains Oral Epithelial Homeostasis.

The oral epithelium is one of the fastest repairing and continuously renewing tissues. Stem cell activation within the basal layer of the oral epithelium fuels the rapid proliferation of multipotent progenitors. Stem cells first undergo asymmetric cell division that requires tightly controlled and orchestrated differentiation networks to maintain the pool of stem cells while producing progenitors fated for differentiation. Rapidly expanding progenitors subsequently commit to advanced differentiation programs towards terminal differentiation, a process that regulates the structural integrity and homeostasis of the oral epithelium. Therefore, the balance between differentiation and terminal differentiation of stem cells and their progeny ensures progenitors commitment to terminal differentiation and prevents epithelial transformation and oral squamous cell carcinoma (OSCC). A recent comprehensive molecular characterization of OSCC revealed that a disruption of terminal differentiation factors is indeed a common OSCC event and is superior to oncogenic activation. Here, we discuss the role of differentiation and terminal differentiation in maintaining oral epithelial homeostasis and define terminal differentiation as a critical tumour suppressive mechanism. We further highlight factors with crucial terminal differentiation functions and detail the underlying consequences of their loss. Switching on terminal differentiation in differentiated progenitors is likely to represent an extremely promising novel avenue that may improve therapeutic interventions against OSCC.

Polyphasic Characterisation of Cedecea colo sp. nov., a New Enteric Bacterium Isolated from the Koala Hindgut.

The Cedecea genus is comprised of six rarely isolated species within the Enterobacteriaceae family. Representatives are Gram-negative motile bacilli, and are typically oxidase-negative, lipase-positive and resistant to colistin and cephalothin. In this study, a putative novel Cedecea species (designated strain ZA_0188T), isolated from the koala hindgut, was characterised using a polyphasic taxonomic approach. Maximum average nucleotide identity (ANI) and 16S ribosomal RNA (rRNA) similarity scores well below thresholds of species demarcation were reported, at 81.1% and 97.9%, respectively. Multilocus phylogenetic analysis indicated strain ZA_0188T was most similar to but divergent from recognised Cedecea species. The isolate's genomic G+C content was determined as 53.0 mol%, >1% lower than previously reported in Cedecea. Phenotypically, strain ZA_0188T was distinct from recognised Cedecea species such as colistin- and cephalothin-sensitive, lipase-, sorbitol-, sucrose-, and Voges-Proskauer-negative, and melibiose-, arabinose-, arginine-, and rhamnose-positive. In preliminary experiments, strain ZA_0188T exhibited cellulase activity and high-level tolerance to eucalyptus oil compared to other enteric species surveyed. Collectively, these findings suggest that strain ZA_0188T represents a novel enteric species, for which the name Cedecea colo is proposed.

Siccibacter turicensis from Kangaroo Scats: Possible Implication in Cellulose Digestion.

Microbiota in the kangaroo gut degrade cellulose, contributing to the kangaroo's energy and survival. In this preliminary study, to discover more about the gut microbes that contribute to the survival of kangaroos, cellulose-degrading bacteria were isolated from kangaroo scats by selection on solidified media containing carboxymethyl cellulose as the main carbon source. One frequently occurring aerobic bacterium was Siccibacter turicensis, a microbe previously isolated in fruit powder and from a patient with angular cheilitis. The whole genome sequence of the kangaroo isolate was obtained using the Illumina MiSeq platform. Its sequence shared 97.98% identity of the S. turicensis Type strain, and the ability of the Type strain to degrade cellulose was confirmed. Analysis of the genomic data focused on the cellulose operon. In addition to genes from the operon, we suggest that a gene following the operon may have an important role in regulating cellulose metabolism by signal transduction. This is the first report of S. turicensis found within microbiota of the animal gut. Because of its frequent presence in the kangaroo gut, we suggest that S. turicensis plays a role in cellulose digestion for kangaroos.

Functionalization of Elongated Tetrahexahedral Au Nanoparticles and Their Antimicrobial Activity Assay.

Gold nanoparticles are inert for the human body, and therefore, they have been functionalized to provide them with antibacterial properties. Here, elongated tetrahexahedral (ETHH) Au nanoparticles were synthesized, characterized, and functionalized with lipoic acid (LA), a natural antioxidant with a terminal carboxylic acid and a dithiolane ring, to generate ETHH-LA Au nanoparticles. The antioxidant activity of Au nanoparticles was investigated in vitro, showing that LA enhances the 2,2-diphenyl-1-picrylhydrazyl free-radical scavenging and Fe3+ ion reducing activity of ETHH-LA at higher amounts. The antimicrobial propensities of the nanoparticles were investigated against Gram-positive ( Bacillus subtilis) and Gram-negative ( Escherichia coli) bacteria through propidium iodide assay as well as disk diffusion assay. ETHH-LA Au nanoparticles showed significantly higher antimicrobial activity against B. subtilis compared with E. coli. Furthermore, ETHH-LA Au nanoparticles also showed significantly better antimicrobial activity against both bacterial strains when compared with ETHH. ETHH Au nanoparticles also bring about the oxidation of bacterial cell membrane fatty acids and produce lipid peroxides. ETHH-LA showed higher lipid peroxidation potential than that of ETHH against both bacteria tested. The hemolytic potential of Au nanoparticles was investigated using human red blood cells and ETHH-LA showed reduced hemolytic activity than that of ETHH. The cytotoxicity of Au nanoparticles was investigated using human cervical cancer cells, HeLa, and ETHH-LA Au nanoparticles showed reduced cytotoxicity than that of ETHH. Taken together, LA enhances the antimicrobial activity of ETHH Au nanoparticles and Au nanoparticles interact with the bacteria through electrostatic interactions as well as hydrophobic interactions and damage the bacterial cell wall followed by oxidation of cell membrane fatty acids.